HIV replication inhibitors

ABSTRACT

This invention concerns HIV replication inhibitors of formula 
                         
the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, provided that when Q is halo then Z is N; or when Q is polyhaloC 1-6 alkyl then Y is hydrogen or C 1-6 alkyl; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a National Stage Application under 35 U.S.C. § 371of PCT/EP01/04991, filed May 3, 2001, which claims priority to U.S.Provisional Application Ser. No. 60/202,472, filed May 8, 2000, all ofwhich are incorporated herein by reference in their entirety.

The present invention concerns substituted amino pyrimidine or triazinederivatives having Human Immunodeficiency Virus (HIV) replicationinhibiting properties. It also relates to their use as a medicine, theirprocesses for preparation and pharmaceutical compositions comprisingthem.

WO 99/50250 and WO 00/27825 disclose substituted amino pyrimidinederivatives having HIV replication inhibiting properties.

EP 0,834,507, WO 99/50256 and WO 00/27828 disclose substituted aminotriazine derivatives having HIV replication inhibiting properties.

WO 95/10506 concerns N-alkyl-N-aryl-pyrimidinamines having antagonisticactivity at the CRF (Corticotropin Releasing Factor) receptor. Saidcompounds are claimed to have a therapeutic effect on psychiatricdisorders and neurological diseases.

EP 0,270,111 describes pyrimidine derivatives having fungicidalactivity.

The present compounds differ from the prior art compounds by theirstructure and by their improved HIV replication inhibiting properties.

The present invention concerns the use of a compound for the manufactureof a medicament for the prevention or the treatment of HIV (HumanImmunodeficiency Virus) infection wherein the compound is a compound offormula (I)

-   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary    amine and a stereochemically isomeric form thereof, wherein-   -a¹=a²-a³=a⁴- represents a bivalent radical of formula    —CH═CH—CH═CH—  (a-1);    —N═CH—CH═CH—  (a-2);    —N═CH—N═CH—  (a-3);    —N═CH—CH═N—  (a-4);    —N═N—CH═CH—  (a-5);-   n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³=a⁴- is (a-1), then n may    also be 5;-   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl;    -   C₁₋₆alkyl substituted with formyl, C₁₋₆alkylcarbonyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;        C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with        C₁₋₆alkyloxycarbonyl;-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,    —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,    —C(═NH)R⁶ or a radical of formula

-   -   wherein each A₁ independently is N, CH or CR⁶; and        -   A₂ is NH, O, S or NR⁶;

-   L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby    each of said groups may be substituted with one or two substituents    independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, polyhalomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein        each of said aromatic rings may optionally be substituted with        one, two, three, four or five substituents each independently        selected from the substituents defined in R²; or

-   L is —X¹—R³ or —X²-Alk-R⁴ wherein    -   Alk is C₁₋₄alkanediyl;    -   R³ or R⁴ each independently are phenyl, pyridyl, pyrimidinyl,        pyrazinyl or pyridazinyl, wherein each of said aromatic rings        may optionally be substituted with one, two, three, four or five        substituents each independently selected from the substituents        defined in R²; and    -   X¹ X² each independently are —NR⁷—, —NH—NH—, —N═N—, —O—,        —C(═O)—, —CHOH—, —S—, —S(═O)_(p)—;

-   Q represents cyano, hydroxy, mercapto, carboxyl, formyl, halo,    cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, mercaptoC₁₋₆alkyl, aminoC₁₋₆alkyl,    mono- or di(C₁₋₄alkyl)-aminoC₁₋₆alkyl, aminocarbonyl, mono- or    di(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,    C₁₋₆alkylS(═O)_(p), C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkenyloxyamino, R⁵—C(═O)—C₁₋₆alkyloxyamino, C₂₋₆alkynyl,    polyhaloC₁₋₆alkyl, hydroxypolyhaloC₁₋₆alkyl, Het or    C₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogen atom may optionally be    substituted with C₁₋₆alkyloxy;

-   Z is C—Y or N wherein    -   Y represents hydrogen, hydroxy, halo, C₁₋₆alkyl, C₃₋₇cycloalkyl,        C₂₋₆alkenyl optionally substituted with one or more halogen        atoms, C₂₋₆alkynyl optionally substituted with one or more        halogen atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁸,        C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,        amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,        polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁸,        —NH—S(═O)_(p)R⁸, —C(═O)R⁸, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁸,        —C(═NH)R⁸ or aryl;

-   R⁵ is hydrogen or a radical of formula

-   -   with A₁ being CH₂ or O;

-   R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   R⁷ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl, C₁₋₆alkyl    carbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl;

-   R⁸ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   p is 1 or 2;

-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkyloxy, aminocarbonyl, tetrazolyl;

-   Het is imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,    isoxazolyl, triazolyl, tetrazolyl optionally substituted with imino,    a radical of formula (c) as described hereinabove, imidazolidinyl,    pyrazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,    isoxazolidinyl optionally substituted with hydroxy, isoxazolidinone,    or a radical of formula

-   -   with A₂ being O, CH₂ or a direct bond;        -   A₃ being CH₂ or NH;        -   A₄ being CH₂ or a direct bond; or        -   A₃-A₄ representing CH═CH;        -   R⁹ being hydrogen or C₁₋₄alkylcarbonyl;

-   provided that when Q is halo then Z is N; or when Q is    polyhaloC₁₋₆alkyl then Y is hydrogen or C₁₋₆alkyl.

As used hereinbefore or hereinafter C₁₋₄alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 4 carbon atoms such as methyl, ethyl, propyl,1-methylethyl, butyl and the like; C₁₋₆alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms such as the group defined for C₁₋₄alkyland pentyl, hexyl, 2-methylbutyl and the like; C₁₋₁₀alkyl as a group orpart of a group defines straight or branched chain saturated hydrocarbonradicals having from 1 to 10 carbon atoms such as the groups defined forC₁₋₆alkyl and heptyl, octyl, nonyl, decyl, 2-methyl-heptyl,3-ethyl-heptyl and the like; C₁₋₄alkanediyl defines straight or branchedchain saturated bivalent hydrocarbon radicals having from 1 to 4 carbonatoms such as methylene, 1,2-ethanediyl or 1,2-ethylidene,1,3-propanediyl or 1,3-propylidene, 1,4-butanediyl or 1,4-butylidene andthe like; C₃₋₇cycloalkyl is generic to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl; C₂₋₆alkenyl defines straightand branched chain hydrocarbon radicals having from 2 to 6 carbon atomscontaining a double bond such as ethenyl, propenyl, butenyl, pentenyl,hexenyl and the like; C₂₋₁₀alkenyl defines straight and branched chainhydrocarbon radicals having from 2 to 10 carbon atoms containing adouble bond such as the groups defined for C₂₋₆alkenyl and heptenyl,octenyl, nonenyl, decenyl and the like; C₂₋₆alkynyl defines straight andbranched chain hydrocarbon radicals having from 2 to 6 carbon atomscontaining a triple bond such as ethynyl, propynyl, butynyl, pentynyl,hexynyl and the like; C₂₋₁₀alkynyl defines straight and branched chainhydrocarbon radicals having from 2 to 10 carbon atoms containing atriple bond such as the groups defined for C₂₋₆alkynyl and heptynyl,octynyl, nonynyl, decynyl and the like.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhalomethyl as a group or part of agroup is defined as mono- or polyhalosubstituted methyl, in particularmethyl with one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₆alkyl as a group or part of a group isdefined as mono- or polyhalosubstituted C₁₋₆alkyl, for example, thegroups defined in halomethyl, 1,1-difluoro-ethyl and the like. In casemore than one halogen atoms are attached to an alkyl group within thedefinition of polyhalomethyl or polyhaloC₁₋₆alkyl, they may be the sameor different.

Het is meant to include all the possible isomeric forms of theheterocycles mentioned in the definition of Het, for instance,imidazolyl also includes 2H-imidazolyl.

The Het radical may be attached to the remainder of the molecule offormula (I) through any ring carbon or heteroatom as appropriate, if nototherwise specified. Thus, for example, when the heterocycle isimidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and thelike.

When any variable (eg. aryl, R², etc.) occurs more than one time in anyconstituent, each definition is independent.

Lines drawn into ring systems from substituents indicate that the bondmay be attached to any of the suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acids as inorganic acids, for example, hydrohalic acids,e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;phosphoric acid and the like; or organic acids, for example, acetic,propanoic, hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic,malonic, succinic, maleic, fumaric, malic, tartaric,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like. Conversely the salt form can be convertedby treatment with acid into the free acid form. The term addition saltalso comprises the hydrates and solvent addition forms which thecompounds of formula (I) are able to form. Examples of such forms aree.g. hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

It will be appreciated that some of the compounds of formula (I) andtheir N-oxides, addition salts, quaternary amines and stereochemicallyisomeric forms may contain one or more centers of chirality and exist asstereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), and their N-oxides, addition salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) and their N-oxides, salts, solvates or quaternary aminessubstantially free, i.e. associated with less than 10%, preferably lessthan 5%, in particular less than 2% and most preferably less than 1% ofthe other isomers. In particular, stereogenic centers may have the R- orS-configuration; substituents on bivalent cyclic (partially) saturatedradicals may have either the cis- or trans-configuration. Compoundsencompassing double bonds can have an E or Z-stereochemistry at saiddouble bond. Stereochemically isomeric forms of the compounds of formula(I) are obviously intended to be embraced within the scope of thisinvention.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto also include their N-oxide forms, their salts, their quaternaryamines and their stereochemically isomeric forms. Of special interestare those compounds of formula (I) which are stereochemically pure.

The invention also concerns a compound of formula (I′)

-   the N-oxides, the pharmaceutically acceptable addition salts, the    quaternary amines and the stereochemically isomeric forms thereof,    wherein-   -b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula    —CH═CH—C(R^(2a))═CH—CH═  (b-1);    —N═CH—C(R^(2a))═CH—CH═  (b-2);    —CH═N—C(R^(2a))═CH—CH═  (b-3);    —N═CH—C(R^(2a))═N—CH═  (b-4);    —N═CH—C(R^(2a))═CH—N═  (b-5);    —CH═N—C(R^(2a))═N—CH═  (b-6);    —N═N—C(R^(2a))═CH—CH═  (b-7);-   q is 0, 1, 2; or where possible q is 3 or 4;-   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl;    -   C₁₋₆alkyl substituted with formyl, C₁₋₆alkylcarbonyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;        C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with        C₁₋₆alkyloxycarbonyl;    -   R^(2a) is cyano, aminocarbonyl, mono- or        di(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano,        aminocarbonyl or mono- or di(methyl)aminocarbonyl, C₂₋₆alkenyl        substituted with cyano, or C₂₋₆alkynyl substituted with cyano;-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,    —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂,    —NHC(═O)R⁶,—C(═NH)R⁶ or a radical of formula

-   -   wherein each A₁ independently is N, CH or CR⁶; and        -   A₂ is NH, O, S or NR⁶;

-   L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby    each of said groups may be substituted with one or two substituents    independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, polyhalomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein        each of said aromatic rings may optionally be substituted with        one, two, three, four or five substituents each independently        selected from the substituents defined in R²; or

-   L is —X¹—R³ or —X²-Alk-R⁴ wherein    -   Alk is C₁₋₄alkanediyl;    -   R³ or R⁴ each independently are phenyl, pyridyl, pyrimidinyl,        pyrazinyl or pyridazinyl, wherein each of said aromatic rings        may optionally be substituted with one, two, three, four or five        substituents each independently selected from the substituents        defined in R²; and    -   X¹ or X² each independently are —NR⁷—, —NH—NH—, —N═N—, —O—,        —C(═O)—, —CHOH—, —S—, —S(═O)_(p)—;

-   Q represents cyano, hydroxy, mercapto, carboxyl, formyl, halo,    cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, mercaptoC₁₋₆alkyl, aminoC₁₋₆alkyl,    mono- or di(C₁₋₄alkyl)-aminoC₁₋₆alkyl, aminocarbonyl, mono- or    di(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,    C₁₋₆alkylS(═O)_(p), C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkenyloxyamino, R⁵—C(═O)—C₁₋₆alkyloxyamino, C₂₋₆alkynyl,    polyhaloC₁₋₆alkyl, hydroxypolyhaloC₁₋₆alkyl, Het or    C₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogen atom may optionally be    substituted with C₁₋₆alkyloxy;

-   Z is C—Y or N wherein    -   Y represents hydrogen, hydroxy, halo, C₁₋₆alkyl, C₃₋₇cycloalkyl,        C₂₋₆alkenyl optionally substituted with one or more halogen        atoms, C₂₋₆alkynyl optionally substituted with one or more        halogen atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁸,        C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,        amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,        polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁸,        —NH—S(═O)_(p)R⁸, —C(═O)R⁸, —NHC(═O)H, —C(═)NHNH₂,        —NHC(═O)R⁸,—C(═NH)R⁸ or aryl;

-   R⁵ is hydrogen or a radical of formula

-   -   with A₁ being CH₂ or O;

-   R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   R⁷ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl;

-   R⁸ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   p is 1 or 2;

-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkyloxy, aminocarbonyl, tetrazolyl;

-   Het is imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,    isoxazolyl, triazolyl, tetrazolyl optionally substituted with imino,    a radical of formula (c) as described hereinabove, imidazolidinyl,    pyrazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,    isoxazolidinyl optionally substituted with hydroxy, isoxazolidinone,    or a radical of formula

-   -   with A₂ being O, CH₂ or a direct bond;        -   A₃ being CH₂ or NH;        -   A₄ being CH₂ or a direct bond; or        -   A₃-A₄ representing CH═CH;        -   R⁹ being hydrogen or C₁₋₄alkylcarbonyl;

-   provided that when Q is halo then Z is N; or when Q is    polyhaloC₁₋₆alkyl then Y is hydrogen or C₁₋₆alkyl.

Another interesting group of compounds are those compounds of formula(I) or (I′) wherein Q is cyano, hydroxy, mercapto, carboxyl, formyl,cyanoC₁₋₆alkyl, hydroxy-C₁₋₆alkyl, mercaptoC₁₋₆alkyl, aminoC₁₋₆alkyl,mono- or di(C₁₋₄alkyl)amino-C₁₋₆alkyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkyloxy-C₁₋₆alkyl wherein each hydrogenatom may optionally be substituted with C₁₋₆alkyloxy, C₁₋₆alkyloxy,C₁₋₆alkylthio, C₁₋₆alkylS(═O)_(p), C₁₋₆alkylcarbonyl,C₁₋₆alkylcarbonyloxy, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkenyloxyamino,R⁵—C(═O)—C₁₋₆alkyloxyamino, C₂₋₆alkynyl, hydroxypolyhaloC₁₋₆alkyl, orHet.

Also an interesting group of compounds are those compounds of formula(I) or (I′) wherein Q is cyano, hydroxy, mercapto, carboxyl,hydroxyC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl, aminocarbonyl,C₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogen atom may optionally besubstituted with C₁₋₆alkyloxy, C₁₋₆alkyloxy, C₁₋₆alkylthio,C₁₋₆alkylS(═O), C₁₋₆alkyloxycarbonyl, halo, polyhaloC₁₋₆alkyl,C₂₋₆alkenyloxyamino, R⁵—C(═O)—C₁₋₆alkyloxyamino, a radical of formula(c) or (e-1) or (e-2), imidazolyl, triazolyl, tetrazolyl optionallysubstituted with imino, isoxazolidinyl optionally substituted withhydroxy, isoxazolidinone.

A further interesting group of compounds are those compounds of formula(I) or (I′) wherein Q is cyano, hydroxy, mercapto, carboxyl,hydroxyC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl, aminocarbonyl,C₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogen atom may optionally besubstituted with C₁₋₆alkyloxy, C₁₋₆alkyloxy, C₁₋₆alkylthio,C₁₋₆alkylS(═O), C₁₋₆alkyloxycarbonyl, C₂₋₆alkenyloxyamino,R⁵—C(═O)—C₁₋₆alkyloxyamino, a radical of formula (c) or (e-1) or (e-2),imidazolyl, triazolyl, tetrazolyl optionally substituted with imino,isoxazolidinyl optionally substituted with hydroxy, isoxazolidinone.

Still a further interesting group of compounds are those compounds offormula (I) or (I′) wherein Z is C—Y.

Still another interesting group of compounds are those compounds offormula (I) or (I′) wherein Z is N.

Also an interesting group of compounds are those compounds of formula(I) or (I′) wherein Z is C—Y and Q is hydroxyC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogenatom may optionally be substituted with C₁₋₆alkyloxy, carboxyl,C₁₋₆alkyloxycarbonyl, polyhaloC₁₋₆alkyl, aminocarbonyl, imidazolyl.

Also an interesting group of compounds are those compounds of formula(I) or (I′) wherein Z is C—Y and Q is hydroxyC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogenatom may optionally be substituted with C₁₋₆alkyloxy, carboxyl,C₁₋₆alkyloxycarbonyl, aminocarbonyl, imidazolyl.

Yet another interesting group of compounds are those compounds offormula (I) or (I′) wherein Z is N and Q is cyano, hydroxy,C₁₋₆alkyloxy, C₁₋₆alkylthio, sulfhydryl, C₁₋₆alkylS(═O), aminocarbonyl,halo, C₂₋₆alkenyloxyamino, R⁵—C(═O)—C₁₋₆alkyloxyamino, a radical offormula (c) or (e-1) or (e-2), imidazolyl, triazolyl, tetrazolyloptionally substituted with imino, isoxazolidinyl optionally substitutedwith hydroxy, isoxazolidinone.

Also an interesting group of compounds are those compounds of formula(I) or (I′) wherein Z is N and Q is cyano, hydroxy, C₁₋₆alkyloxy,C₁₋₆alkylthio, sulfhydryl, C₁₋₆alkylS(═O), aminocarbonyl,C₂₋₆alkenyloxyamino, R⁵—C(═O)—C₁₋₆alkyloxyamino, a radical of formula(c) or (e-1) or (e-2), imidazolyl, triazolyl, tetrazolyl optionallysubstituted with imino, isoxazolidinyl optionally substituted withhydroxy, isoxazolidinone.

Yet another interesting group of compounds are those compounds offormula (I) or (I′) wherein L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, whereby each of said groups may be substituted with oneor two substituents independently selected from C₃₋₇cycloalkyl; indolylor isoindolyl, each optionally substituted with one, two, three or foursubstituents each independently selected from halo, C₁₋₆alkyl, hydroxy,C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl,polyhalomethyloxy and C₁₋₆alkylcarbonyl; phenyl, pyridyl, pyrimidinyl,pyrazinyl or pyridazinyl, wherein each of said aromatic rings mayoptionally be substituted with one, two, three, four or fivesubstituents each independently selected from the substituents definedin R²; or L is —X¹—R³.

Still another interesting group of compounds are those compounds offormula (I) or (I′) wherein Y is hydroxy, halo, C₃₋₇cycloalkyl,C₂₋₆alkenyl optionally substituted with one or more halogen atoms,C₂₋₆alkynyl optionally substituted with one or more halogen atoms,C₁₋₆alkyl substituted with cyano or —C(═O)R⁸, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁸, —NH—S(═O)_(p)R⁸, —C(═O)R⁸, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁸,—C(═NH)R⁸ or aryl.

Also an interesting group of compounds are those compounds of formula(I) wherein -a¹=a²-a³=a⁴-represents a bivalent radical of formula—CH═CH—CH═CH—  (a-1)or—N═CH—CH═CH—  (a-2).

Also an interesting group of compounds are those compounds of formula(I′) wherein -b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical offormula—CH═CH—C(R^(2a))═CH—CH═  (b-1)or—CH═N—C(R^(2a))═CH—CH═  (b-3).

Still another interesting group of compounds are those compounds offormula (I) or (I′) wherein L is —X—R³ wherein R³ is2,4,6-trisubstituted phenyl, wherein each substituent is independentlyselected from chloro, bromo, fluoro, cyano or C₁₋₄alkyl.

Particular compounds are those compounds of formula (I) or (I′) whereinthe moiety in the 2 position of the pyrimidine ring is a 4-cyano-anilinogroup or a 4-aminocarbonyl-anilino group.

Preferred compounds are those compounds of formula (I) or (I′) whereinthe moiety in the 2 position of the pyrimidine ring is a 4-cyano-anilinogroup, L is —X—R³ wherein R³ is a 2,4,6-trisubstituted phenyl, Z is N orC—Y with Y being halo or hydrogen and Q is hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, cyano or Het.

Preferred compounds of formula (I) or (I′) are selected from

-   4-[[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-hydroxymethyl]-2-pyrimidinyl]amino]benzonitrile;-   4-[[[6-chloro-4-(2,4,6-trimethylphenylamino)]-1,3,5-triazin-2-yl]amino]benzonitrile;-   4-[[[6-trifluoromethyl-2-(4-cyanophenylamino)]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile;-   6-[(4-cyanophenyl)amino]-4-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazine-2-carboxamide;-   4-[[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-methoxymethyl]-2-pyrimidinyl]amino]benzonitrile;-   4-[[[5-bromo-4-(4-cyano-2,6-dibromophenoxy)-6-hydroxymethyl]2-pyrimidinyl]amino]benzonitrile;-   2-[(4-cyanophenyl)amino]-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidine    carboxamide;-   5-bromo-2-[(4-cyanophenyl)amino]-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidine    carboxamide;-   their N-oxides, pharmaceutically acceptable addition salts,    quaternary amines and stereochemically isomeric forms thereof.

In general, compounds of formula (I) can be prepared by reacting anintermediate of formula (II) wherein W₁ is a suitable leaving group suchas, for example, a halogen, hydroxy, triflate, tosylate, thiomethyl,methylsulfonyl, trifluoromethylsulfonyl and the like, with an aminoderivative of formula (III) under solvent-free conditions or in asuitable solvent such as, for example, water, ethanol,1-methyl-2-pyrrolidinone, N,N-dimethylformamide, 1,4-dioxane,1,2-dimethoxy-ethane, tetrahydrofuran, dimethyl sulfoxide, tetraline,sulfolane, acetonitrile, toluene and the like, optionally under areaction-inert atmosphere such as, for example, oxygen free argon ornitrogen, optionally in the presence of a suitable acid such as, forexample, 1 N hydrochloric acid in diethyl ether or the like or asuitable base, such as N,N-diisopropylethanamine, NaI, BuOH, andoptionally in the presence of a suitable catalyst, such as for exampletetrakis(triphenylphosphine) palladium. This reaction can be performedat a temperature ranging between 50° C. and 250° C.

Alternatively, a compound of formula (I) wherein L representsC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby each ofsaid groups may be substituted with one or two substituentsindependently selected from C₃₋₇cycloalkyl; indolyl or isoindolyl, eachoptionally substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxyand C₁₋₆alkylcarbonyl; phenyl, pyridyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein each of said aromatic rings may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the substituents defined in R², said L beingrepresented by L_(a), and said compounds being represented by formula(I-a), can also be prepared by reacting an intermediate of formula (III)with an intermediate of formula (IV) and an intermediate of formula (V)in the presence of magnesium and in the presence of a suitable solventsuch as diethylether, benzene, 1,4-dioxane, N,N-diethylethanamine.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, distillation, trituration andchromatography.

The compounds of formula (I) wherein L is a radical of formula —NR⁷—R³,said compounds being represented by formula (I-b), can be prepared byreacting an intermediate of formula (VI) wherein W₂ is a suitableleaving group such as, for example, a halogen or a triflate, with anintermediate of formula (VII) under solvent-free conditions or in anappropriate solvent such as, for example, ethanol,1-methyl-2-pyrrolidinone, N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, dimethyl sulfoxide, tetraline, sulfolane, acetonitrileand the like, under a reaction-inert atmosphere such as, for example,oxygen free argon or nitrogen, and optionally in the presence of asuitable acid such as, for example, 1 N hydrochloric acid in diethylether or the like or a suitable base, such as N,N-diisopropylethanamine.This reaction can be performed at a temperature ranging between 50° C.and 250° C.

The compounds of formula (I) wherein L is a radical of formula —X¹—R³ or—X²-Alk-R⁴, said L being represented by L_(b), and said compounds beingrepresented by formula (I-c), can be prepared by reacting anintermediate of formula (VI) wherein W₂ is a suitable leaving group suchas, for example a halogen or a triflate, with an intermediate of formula(VIIII) in an appropriate solvent such as, for example,1-methyl-2-pyrrolidinone, 1,4-dioxane, dimethyl sulfoxide, tetraline,sulfolane, tetrahydrofuran, acetone, acetone/water and the like under areaction-inert atmosphere such as, for example, oxygen free argon ornitrogen, and in the presence of a suitable base such as, for example,sodium hydride, potassium hydride, sodium hydroxide,N,N-diisopropylethanamine or the like. This reaction can be performed ata temperature ranging between 50° C. and 250° C.

The compounds of formula (I) wherein Q is a radical of formula (e-1),said compounds being represented by formula (I-d), can be prepared byreacting an intermediate of formula (IX-a) with an intermediate offormula (X), wherein W₃ represents a suitable leaving group, such as ahalogen, e.g. chloro, bromo and the like.

The compounds of formula (I), wherein Q is a radical of formula (e-2),said compounds being represented by formula (I-e), can be prepared bycycling an intermediate of formula (IX-b) in the presence of a suitablecarbonic derivative, such as for example acetic acid anhydride, and inthe presence of a suitable base, such as sodium acetate.

The compounds of formula (I-e), wherein A₃ is NH and A₄ is a directbond, said compounds being represented by formula (I-e-1), can beprepared by reacting an intermediate of formula (IX-c) with a carbonicderivative, such as for example carbonic dichloride, in the presence ofa suitable solvent, such as for example dioxane.

The compounds of formula (I), wherein Q is isoxazolidinone, saidcompounds being represented by formula (I-f), can be prepared byreacting an intermediate of formula (IX-d) with W₄—CH₂—CH₂—C(═O)—W₄,wherein W₄ represents a suitable leaving group, such as a halogen, e.g.chloro, bromo and the like, in the presence of a suitable base, such asfor example N N-diethylethanamine, and a suitable solvent, such astetrahydrofuran.

The compounds of formula (I) wherein Z is N, said compounds beingrepresented by formula (I-g), can be prepared by reacting anintermediate of formula (XXIII) with an intermediate of formula (XXIV)and an intermediate of formula (XXV) in the presence of a suitable base,such as for example sodium acetate or Na₂CO₃, and a suitable solvent,such as acetonitrile.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

For instance, compounds of formula (I) wherein Q is halo, can beconverted into a compound of formula (I) wherein Q is cyano, by reactionwith a suitable cyano-introducing agent, such as sodium cyanide orcopper(I) cyanide, optionally in the presence of a suitable catalyst,such as for example tetrakis(triphenylphosphine) palladium and in thepresence of a suitable solvent, such as N,N-dimethyl-aniline or1-methyl-2-pyrrolidinone. A compound of formula (I) wherein Q is cyano,can further be converted into a compound of formula (I) wherein Q isaminocarbonyl, by reaction with HCOOH, in the presence of a suitableacid, such as hydrochloric acid. A compound of formula (I) wherein Q andR² are both cyano, can be converted into a compound of formula (I)wherein Q and R² are both aminocarbonyl by reaction with HCOOH, in thepresence of a suitable acid, such as hydrochloric acid. A compound offormula (I) wherein Q is cyano, can also further be converted into acompound of formula (I) wherein Q is tetrazolyl, by reaction with sodiumazide in the presence of ammonium chloride andN,N-dimethylacetoacetamide.

Compounds of formula (I) wherein Q is halo can also be converted into acompound of formula (I) wherein Q is mercapto, by reaction with disodiumsulfide in the presence of a suitable solvent, such as, for example,1,4-dioxane.

Compounds of formula (I) wherein Q is halo can also be converted into acompound of formula (I) wherein Q is C₁₋₆alkylthio, by reaction with asuitable reagent such as alkaline metal-S—C₁₋₆alkyl, e.g.sodium-S—C₁₋₆alkyl, in the presence of a suitable solvent, such asN,N-dimethyl sulfoxide. The latter compounds of formula (I) can furtherbe converted into a compound of formula (I) wherein Q isC₁₋₆alkyl-S(═O)—, by reaction with a suitable oxidizing agent, such as aperoxide, e.g. 3-chlorobenzenecarboperoxoic acid, in the presence of asuitable solvent, such as an alcohol, e.g. ethanol.

Compounds of formula (I) wherein Q is halo can also be converted into acompound of formula (I) wherein Q is C₁₋₆alkyloxy, by reaction with, forexample, LiOC₁₋₆alkyl, in the presence of a suitable solvent, such as analcohol, e.g. methanol.

Compounds of formula (I) wherein Q is halo can also be converted into acompound of formula (I) wherein Q is hydroxy, by reaction with asuitable carboxylate ester, e.g. sodium acetate, in a suitablereaction-inert solvent, such as, for example, N,N-dimethyl sulfoxide,followed by treating the obtained reaction product with a suitable base,such as pyridine, and acetyl chloride.

Compounds of formula (I) wherein Q is halo can also be converted into acompound of formula (I) wherein Q represents imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, tetrazolyloptionally substituted with imino, a radical of formula (c),imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl,oxazolidinyl, isoxazolidinyl optionally substituted with hydroxy,isoxazolidinone, said Q being represented by -Q_(b), by reaction withH-Q_(b) in the presence of a suitable base, such as, for example sodiumhydroxide, potassium carbonate, sodium hydride, in the presence of asuitable solvent, such as, for example, 1,4-dioxane,N,N-dimethylacetamide, N,N-dimethylformamide

Compounds of formula (I) wherein Q is chloro, can be converted into acompound of formula (I) wherein Q is fluoro, by reaction with a suitablefluoride salt, such as for example potassium fluoride, in the presenceof a suitable solvent, e.g. sulfolane.

Compounds of formula (I) wherein Q represents C₁₋₆alkyloxyC₁₋₆alkyl, canbe converted into a compound of formula (I) wherein Q representshydroxyC₁₋₆alkyl, by reducing the ether in the presence of a suitableagent, such as, for example, tribromoborane, and a suitable solvent,such as methylene chloride. Compounds of formula (I) wherein Qrepresents hydroxyC₁₋₆alkyl can be converted into a compound of formula(I) wherein Q represents haloC₁₋₆alkyl by reaction with a suitablehalo-introducing agent, such as for example SOCl₂, in the presence of asuitable solvent, such as tetrahydrofuran and a suitable base, such asfor example N,N-diethylethanamine. Compounds of formula (I) wherein Qrepresents haloC₁₋₆alkyl can be converted into a compound of formula (I)wherein Q represents mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl, by reactionwith a suitable amine, such as a mono- or di(C₁₋₄alkyl)amine.

Compounds of formula (I) wherein Q represents C₁₋₆alkyloxycarbonyl, canbe converted into a compound of formula (I) wherein Q representsaminocarbonyl or mono- or di(C₁₋₄alkyl)aminocarbonyl by reaction with asuitable agent such as ammonia, NH₂(C₁₋₄alkyl), AlCH₃[N(C₁₋₄alkyl)₂]Cloptionally in the presence of a suitable acid, such as for examplehydrochloric acid, and in the presence of a suitable solvent such as analcohol, e.g. methanol, tetrahydrofuran, N,N-diisopropylethanamine, analcohol, e.g. methanol. Compounds of formula (I) wherein Q representsC₁₋₆alkyloxycarbonyl, can also be converted into a compound of formula(I) wherein Q represents carboxyl by reaction with a suitable base, suchas for example LiOH and the like, in the presence of a suitable solvent,such as for example an alcohol, e.g. methanol, and water.

Compounds of formula (I) wherein Q represents carboxyl can be convertedinto a compound of formula (I) wherein Q represents aminocarbonyl ormono-or di(C1-4alkyl)aminocarbonyl, by reaction with a suitable agentsuch as ammonia, ammonium chloride, NH₂(C₁₋₄alkyl),AlCH₃[N(C₁₋₄alkyl)₂]Cl in the presence of SOCl₂ and a suitable solvent,such as for example N,N-dimethylformamide and water.

Compounds of formula (I) wherein Q is a radical of formula (e-2),wherein R⁹ is C₁₋₄alkylcarbonyl, can be converted into a compound offormula (I) wherein Q is a radical of formula (e-2), wherein R⁹ ishydrogen, in the presence of a suitable solvent, such as an alcohol,e.g. methanol.

Compounds of formula (I) wherein Y is hydrogen can be converted into acompound wherein Y is halo, by reaction with a suitable halogenatingagent, such as, for example Br₂ or1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2,2,2]octanebis[tetrafluoro-borate], in the presence of a suitable solvent, such astetrahydrofuran, water, acetontrile, chloroform and optionally in thepresence of a suitable base such as N,N-diethylethanamine or a suitableacid, such as for example acetic acid. The same type of reaction can beused to introduce a halo atom as R².

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures or some of the compounds of formula (I) or the describedintermediates may be prepared according to the procedures described inEP-0834507, WO99/50250, WO99/50256, WO 00/27825 and WO 00/27828.

Intermediates of formula (II) wherein L is —X¹—R³ or —X²-Alk-R⁴, said Lbeing represented by -L_(b), and said intermediates being represented byformula (II-a), can be prepared by reacting an intermediate of formula(IV) wherein each W¹ is as defined previously, with an intermediate offormula (VIII) in the presence of a suitable solvent such as, forexample, 1,4-dioxane, 2-propanol, acetone or the like, and in thepresence of a suitable base such as, for example, N,N-diethylethanamineor N,N-diisopropylethanamine, K₂CO₃, NaI or the like.

Intermediates of formula (II) wherein Q is Het, said intermediates beingrepresented by formula (II-b), can be prepared by reacting anintermediate of formula (II-c) wherein W₁ is as previously defined, withH-Het in the presence of a suitable solvent, such as for exampleN,N-dimethylacetamide and a suitable base, such as for exampledipotassium carbonate.

Intermediates of formula (VI) can be prepared by reacting anintermediate of formula (IV-a) wherein W₂ is a suitable leaving groupsuch as, for example, a halogen, with an intermediate of formula (III)in the presence of a suitable solvent such as, for example,1-methyl-2-pyrrolidinone, 1,4-dioxane, tetrahydrofuran or the like, inthe presence of a suitable acid such as, for example, 1 N hydrochloricacid in diethyl ether or a suitable base, such as for exampleN,N-diethylethanamine. This reaction can be performed at a temperatureranging between 50° C. and 250° C.

Alternatively, intermediates of formula (VI) can be prepared by reactingan intermediate of formula (XII) with a leaving group introducing agentof formula (XI), wherein W₂ represents the leaving group and Rrepresents the remaining of the leaving group introducing agent, anexample of a suitable leaving group introducing agent of formula (XI) isphosphorous oxychloride. The reaction can be performed under areaction-inert atmosphere such as, for example, oxygen free argon ornitrogen and at a temperature ranging between 20° C. and 150° C.

Intermediates of formula (XII) can be prepared by reacting anintermediate of formula (XIII) or a functional derivative thereof, withan intermediate of formula (III). This reaction may be performed undersolvent-free conditions or in an appropriate solvent such as, forexample, diglyme, tetraline or the like under a reaction-inertatmosphere such as, for example, oxygen free argon or nitrogen, andoptionally in the presence of a base such as, for example, sodiumhydride, potassium hydride or the like. This reaction can be performedat a temperature ranging between 100° C. and 250° C.

Intermediates of formula (XII) can also be prepared by reacting anintermediate of formula (XIV) wherein W₃ is a suitable leaving group,such as for example C₁₋₆alkyloxy, and Z and Q are as defined for acompound of formula (I), with an intermediate of formula (XV) in anappropriate solvent such as an alcohol, for example ethanol, or thelike, and in the presence of a suitable base such as, for example,sodium ethoxide or the like, under a reaction-inert atmosphere such as,for example, oxygen free argon or nitrogen. The reaction can beperformed at a temperature ranging between 20° C. and 125° C.

A convenient way of preparing an intermediate of formula (VI) wherein Zis C—Y and Y is a bromine or chloro atom, said intermediates beingrepresented by formula (VI-a), involves the introduction of a bromine orchloro atom to an intermediate of formula (XVI), wherein W₂ is aspreviously defined, using N-bromosuccinimide or N-chlorosuccinimide in areaction-inert solvent such as, for example, chloroform, carbontetrachloride or the like. This reaction can be performed at atemperature ranging between 20° C. and 125° C.

Intermediates of formula (IX-a) wherein Z is N, said intermediates beingrepresented by formula (IX-a-1), can be prepared by reacting anintermediate of formula (XVII) with an intermediate of formula (XVIII)wherein W₅ is a suitable leaving group, such as for example phenoxy, ina suitable solvent, such as for example N,N-dimethylformamide.

Intermediates of formula (XVIII) can be prepared by reacting anintermediate of formula (XIX) with an intermediate of formula (XX) inthe presence of a suitable solvent, such as for exampleN,N-dimethylformamide, under a reaction-inert atmosphere such as, forexample, oxygen free argon or nitrogen, preferably at elevatedtemperatures.

Intermediates of formula (IX-b) wherein -A₃-A₄-represents —CH═CH—, saidintermediates being represented by formula (IX-b-1), can be prepared byreacting an intermediate of formula (XXI) with 2,5-furandione in thepresence of a suitable solvent, such as for example tetrahydrofuran.

Intermediates of formula (IX-c) can be prepared by reacting a compoundof formula (I-g) with an intermediate of formula (XXII) in the presenceof a suitable solvent, such as for example pyridine or an alkanol, e.g.ethanol and the like, and a suitable base, such as for example sodiumhydroxide.

Intermediates of formula (XXIII) can be prepared by hydrolyzing anintermediate of formula (XXVI) in the presence of a suitable acid, suchas hydrochloric acid and the like, and a suitable solvent, such as forexample dioxane.

Intermediates of formula (XXVI) can be prepared by cyclizing anintermediate of formula (XXVII) in the presence of diiodo-methane and inthe presence of a suitable base such as K₂CO₃ and a suitable solvent,such as for example 2-propanone.

Intermediates of formula (XXVII) can be prepared by reacting anintermediate of formula (III) with phosphor(isothiocyanatidic) acid,diphenyl ester in the presence of a suitable solvent, such as forexample methylene chloride.

The compounds of formula (I) as prepared in the hereinabove describedprocesses may be synthesized as a mixture of stereoisomeric forms, inparticular in the form of racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₁₋₆alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after a reaction step.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’ 2^(nd) edition, T W Greene & PG M Wutz, Wiley Interscience (1991).

The compounds of formula (I) and (I′) show antiretroviral properties(reverse transcriptase inhibiting properties), in particular againstHuman Immunodeficiency Virus (HIV), which is the aetiological agent ofAcquired Immune Deficiency Syndrome (AIDS) in humans. The HIV viruspreferentially infects human T-4 cells and destroys them or changestheir normal function, particularly the coordination of the immunesystem. As a result, an infected patient has an everdecreasing number ofT-4 cells, which moreover behave abnormally. Hence, the immunologicaldefense system is unable to combat infections and neoplasms and the HIVinfected subject usually dies by opportunistic infections such aspneumonia, or by cancers. Other conditions associated with HIV infectioninclude thrombocytopaenia, Kaposi's sarcoma and infection of the centralnervous system characterized by progressive demyelination, resulting indementia and symptoms such as, progressive dysarthria, ataxia anddisorientation. HIV infection further has also been associated withperipheral neuropathy, progressive generalized lymphadenopathy (PGL) andAIDS-related complex (ARC).

The present compounds also show activity against multi drug resistantHIV strains, in particular multi drug resistant HIV-1 strains, more inparticular the present compounds show activity against HIV strains,especially HIV-1 strains, that have acquired resistance to art-knownnon-nucleoside reverse transcriptase inhibitors. Art-knownnon-nucleoside reverse transcriptase inhibitors are those non-nucleosidereverse transcriptase inhibitors other than the present compounds. Thepresent compounds also have little or no binding affinity to human α-1acid glycoprotein.

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds offormula (I) or (I′), their N-oxides, pharmaceutically acceptableaddition salts, quaternary amines and stereochemically isomeric formsthereof, are useful in the treatment of individuals infected by HIV andfor the prophylaxis of these infections. In general, the compounds ofthe present invention may be useful in the treatment of warm-bloodedanimals infected with viruses whose existence is mediated by, or dependsupon, the enzyme reverse transcriptase. Conditions which may beprevented or treated with the compounds of the present invention,especially conditions associated with HIV and other pathogenicretroviruses, include AIDS, AIDS-related complex (ARC), progressivegeneralized lymphadenopathy (PGL), as well as chronic CNS diseasescaused by retroviruses, such as, for example HIV mediated dementia andmultiple sclerosis.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines against above-mentioned conditions. Saiduse as a medicine or method of treatment comprises the systemicadministration to HIV-infected subjects of an amount effective to combatthe conditions associated with HIV and other pathogenic retroviruses,especially HIV-1. In particular, the compounds of formula (I) or (I′)may be used in the manufacture of a medicament for the treatment or theprevention of HIV infections.

In view of the utility of the compounds of formula (I) or (I′), there isprovided a method of treating warm-blooded animals, including humans,suffering from or a method of preventing warm-blooded animals, includinghumans, to suffer from viral infections, especially HIV infections. Saidmethod comprises the administration, preferably oral administration, ofan effective amount of a compound of formula (I) or (I′), a N-oxideform, a pharmaceutically acceptable addition salt, a quaternary amine ora possible stereoisomeric form thereof, to warm-blooded animals,including humans.

The present invention also provides compositions for treating viralinfections comprising a therapeutically effective amount of a compoundof formula (I) or (I′) and a pharmaceutically acceptable carrier ordiluent.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. Thecompounds of the present invention may also be administered viainhalation or. insufflation by means of methods and formulationsemployed in the art for administration via this way. Thus, in generalthe compounds of the present invention may be administered to the lungsin the form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

To aid solubility of the compounds of formula (I) or (I′), suitableingredients, e.g. cyclodextrins, may be included in the compositions.Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers andmixed ethers thereof wherein one or more of the hydroxy groups of theanhydroglucose units of the cyclodextrin are substituted with C₁₋₆alkyl,particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl orhydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl orcarboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Theaverage substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The M.S. and D.S. valuecan be determined by various analytical techniques such as nuclearmagnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative.Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration compriseparticles consisting of a solid dispersion comprising a compound offormula (I) or (I′) and one or more appropriate pharmaceuticallyacceptable water-soluble polymers.

The term “a solid dispersion” used hereinafter defines a system in asolid state (as opposed to a liquid or gaseous state) comprising atleast two components, in casu the compound of formula (I) or (I′) andthe water-soluble polymer, wherein one component is dispersed more orless evenly throughout the other component or components (in caseadditional pharmaceutically acceptable formulating agents, generallyknown in the art, are included, such as plasticizers, preservatives andthe like). When said dispersion of the components is such that thesystem is chemically and physically uniform or homogenous throughout orconsists of one phase as defined in thermo-dynamics, such a soliddispersion will be called “a solid solution”. Solid solutions arepreferred physical systems because the components therein are usuallyreadily bioavailable to the organisms to which they are administered.This advantage can probably be explained by the ease with which saidsolid solutions can form liquid solutions when contacted with a liquidmedium such as the gastro-intestinal juices. The ease of dissolution maybe attributed at least in part to the fact that the energy required fordissolution of the components from a solid solution is less than thatrequired for the dissolution of components from a crystalline ormicrocrystalline solid phase.

The term “a solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase. For example, the term “a solid dispersion” also relates to asystem having domains or small regions wherein amorphous,microcrystalline or crystalline compound of formula (I) or (I′), oramorphous, microcrystalline or crystalline water-soluble polymer, orboth, are dispersed more or less evenly in another phase comprisingwater-soluble polymer, or compound of formula (I) or (I′), or a solidsolution comprising compound of formula (I) or (I′) and water-solublepolymer. Said domains are regions within the solid dispersiondistinctively marked by some physical feature, small in size, and evenlyand randomly distributed throughout the solid dispersion.

Various techniques exist for preparing solid dispersions includingmelt-extrusion, spray-drying and solution-evaporation.

The solution-evaporation process comprises the following steps:

-   -   a) dissolving the compound of formula (I) or (I′) and the        water-soluble polymer in an appropriate solvent, optionally at        elevated temperatures;    -   b) heating the solution resulting under point a), optionally        under vacuum, until the solvent is evaporated. The solution may        also be poured onto a large surface so as to form a thin film,        and evaporating the solvent therefrom.

In the spray-drying technique, the two components are also dissolved inan appropriate solvent and the resulting solution is then sprayedthrough the nozzle of a spray dryer followed by evaporating the solventfrom the resulting droplets at elevated temperatures.

The preferred technique for preparing solid dispersions is themelt-extrusion process comprising the following steps:

-   -   a) mixing a compound of formula (I) or (I′) and an appropriate        water-soluble polymer,    -   b) optionally blending additives with the thus obtained mixture,    -   c) heating and compounding the thus obtained blend until one        obtains a homogenous melt,    -   d) forcing the thus obtained melt through one or more nozzles;        and    -   e) cooling the melt till it solidifies.

The terms “melt” and “melting” should be interpreted broadly. Theseterms not only mean the alteration from a solid state to a liquid state,but can also refer to a transition to a glassy state or a rubbery state,and in which it is possible for one component of the mixture to getembedded more or less homogeneously into the other. In particular cases,one component will melt and the other component(s) will dissolve in themelt thus forming a solution, which upon cooling may form a solidsolution having advantageous dissolution properties.

After preparing the solid dispersions as described hereinabove, theobtained products can be optionally milled and sieved.

The solid dispersion product may be milled or ground to particles havinga particle size of less than 600 μm, preferably less than 400 μm andmost preferably less than 125 μm.

The particles prepared as described hereinabove can then be formulatedby conventional techniques into pharmaceutical dosage forms such astablets and capsules.

It will be appreciated that a person of skill in the art will be able tooptimize the parameters of the solid dispersion preparation techniquesdescribed above, such as the most appropriate solvent, the workingtemperature, the kind of apparatus being used, the rate of spray-drying,the throughput rate in the melt-extruder

The water-soluble polymers in the particles are polymers that have anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa·s more preferably of 1 to 700 mPa·s, and mostpreferred of 1 to 100 mPa·s. For example, suitable water-solublepolymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts ofcarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-,oligo- and polysaccharides such as trehalose, alginic acid or alkalimetal and ammonium salts thereof, carrageenans, galactomannans,tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,polyacrylic acids and the salts thereof, polymethacrylic acids and thesalts thereof, methacrylate copolymers, polyvinylalcohol,polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinylacetate, combinations of polyvinylalcohol and polyvinylpyrrolidone,polyalkylene oxides and copolymers of ethylene oxide and propyleneoxide. Preferred water-soluble polymers are hydroxypropylmethylcelluloses.

Also one or more cyclodextrins can be used as water soluble polymer inthe preparation of the above-mentioned particles as is disclosed in WO97/18839. Said cyclodextrins include the pharmaceutically acceptableunsubstituted and substituted cyclodextrins known in the art, moreparticularly α, β or γ cyclodextrins or the pharmaceutically acceptablederivatives thereof.

Substituted cyclodextrins which can be used to prepare the abovedescribed particles include polyethers described in U.S. Pat. No.3,459,731. Further substituted cyclodextrins are ethers wherein thehydrogen of one or more cyclodextrin hydroxy groups is replaced byC₁₋₆alkyl, hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl orC₁₋₆alkyloxycarbonyl-C₁₋₆alkyl or mixed ethers thereof. In particularsuch substituted cyclodextrins are ethers wherein the hydrogen of one ormore cyclodextrin hydroxy groups is replaced by C₁₋₃alkyl,hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or more in particular by methyl,ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl orcarboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g.dimethyl-β-cyclodextrin as described in Drugs of the Future, Vol. 9, No.8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropylβ-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such analkyl ether may be a methyl ether with a degree of substitution of about0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin mayfor example be formed from the reaction between β-cyclodextrin anpropylene oxide and may have a MS value of about 0.125 to 10, e.g. about0.3 to 3.

Another type of substituted cyclodextrins is sulfobutylcyclodextrines.

The ratio of the compound of formula (I) or (I′) over the water solublepolymer may vary widely. For example ratios of 1/100 to 100/1 may beapplied. Interesting ratios of the compound of formula (I) or (I′) overcyclodextrin range from about 1/10 to 10/1. More interesting ratiosrange from about 1/5 to 5/1.

It may further be convenient to formulate the compounds of formula (I)or (I′) in the form of nanoparticles which have a surface modifieradsorbed on the surface thereof in an amount sufficient to maintain aneffective average particle size of less than 1000 nm. Useful surfacemodifiers are believed to include those which physically adhere to thesurface of the compound of formula (I) or (I′) but do not chemicallybond to said compound.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

Yet another interesting way of formulating the compounds of formula (I)or (I′) involves a pharmaceutical composition whereby the compounds offormula (I) or (I′) are incorporated in hydrophilic polymers andapplying this mixture as a coat film over many small beads, thusyielding a composition which can conveniently be manufactured and whichis suitable for preparing pharmaceutical dosage forms for oraladministration.

Said beads comprise a central, rounded or spherical core, a coating filmof a hydrophilic polymer and a compound of formula (I) or (I′) andoptionally a seal-coating layer.

Materials suitable for use as cores in the beads are manifold, providedthat said materials are pharmaceutically acceptable and have appropriatedimensions and firmness. Examples of such materials are polymers,inorganic substances, organic substances, and saccharides andderivatives thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) or (I′) used, the particularcondition being treated, the severity of the condition being treated,the age, weight and general physical condition of the particular patientas well as other medication the individual may be taking, as is wellknown to those skilled in the art. Furthermore, it is evident that saideffective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines and are not intended to limit the scope or use of theinvention to any extent.

The present compounds of formula (I) or (I′) can be used alone or incombination with other therapeutic agents, such as anti-virals,antibiotics, immunomodulators or vaccines for the treatment of viralinfections. They may also be used alone or in combination with otherprophylactic agents for the prevention of viral infections. The presentcompounds may be used in vaccines and methods for protecting individualsagainst viral infections over an extended period of time. The prodrugsmay be employed in such vaccines either alone or together with othercompounds of this invention or together with other anti-viral agents ina manner consistent with the conventional utilization of reversetranscriptase inhibitors in vaccines. Thus, the present compounds may becombined with pharmaceutically acceptable adjuvants conventionallyemployed in vaccines and administered in prophylactically effectiveamounts to protect individuals over an extended period of time againstHIV infection.

Also, the combination of an antiretroviral compound and a compound offormula (I) or (I′) can be used as a medicine. Thus, the presentinvention also relates to a product containing (a) a compound of formula(I) or (I′), and (b) another antiretroviral compound, as a combinedpreparation for simultaneous, separate or sequential use in anti-HIVtreatment. The different drugs may be combined in a single preparationtogether with pharmaceutically acceptable carriers. Said otherantiretroviral compounds may be known antiretroviral compounds such assuramine, pentamidine, thymopentin, castanospermine, dextran (dextransulfate), foscarnet-sodium (trisodium phosphono formate); nucleosidereverse transcriptase inhibitors, e.g. zidovudine(3′-azido-3′-deoxythymidine, AZT), didanosine (2′,3′-dideoxyinosine;ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine(2′-3′-dideoxy-3′-thiacytidine, 3TC), stavudine(2′,3′-didehydro-3′-deoxythymidine, d4T), abacavir and the like;non-nucleoside reverse transciptase inhibitors such as nevirapine(11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one), efavirenz, delavirdine, TMC-120, TMC-125and the like; compounds of the TIBO(tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;compounds of the α-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitrophenyl)amino]-2,6-dichlorobenzene-acetamide and the like;inhibitors of trans-activating proteins, such as TAT-inhibitors, e.g.RO-5-3335, or REV inhibitors, and the like; protease inhibitors e.g.indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir,amprenavir, TMC-126, BMS-232632, VX-175 and the like; fusion inhibitors,e.g. T-20, T-1249, AMD-3100 and the like; inhibitors of the viralintegrase; nucleotide reverse transcriptase inhibitors, e.g. tenofovirand the like; ribonucleotide reductase inhibitors, e.g. hydroxyurea andthe like.

By administering the compounds of the present invention with otheranti-viral agents which target different events in the viral life cycle,the therapeutic effect of these compounds can be potentiated.Combination therapies as described above exert a synergistic effect ininhibiting HIV replication because each component of the combinationacts on a different site of HIV replication. The use of suchcombinations may reduce the dosage of a given conventionalanti-retroviral agent which would be required for a desired therapeuticor prophylactic effect as compared to when that agent is administered asa monotherapy. These combinations may reduce or eliminate the sideeffects of conventional single anti-retroviral therapy while notinterfering with the anti-viral activity of the agents. Thesecombinations reduce potential of resistance to single agent therapies,while minimizing any associated toxicity. These combinations may alsoincrease the efficacy of the conventional agent without increasing theassociated toxicity.

The compounds of the present invention may also be administered incombination with immunomodulating agents, e.g. levamisole, bropirimine,anti-human alpha interferon antibody, interferon alpha, interleukin 2,methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor,naltrexone and the like; antibiotics, e.g. pentamidine isethiorate andthe like; or cholinergic agents, e.g. tacrine, rivastigmine, donepezil,galantamine and the like to prevent or combat infection and diseases orsymptoms of diseases associated with HIV infections, such as AIDS andARC, e.g. dementia. A compound of formula (I) or (I′) can also becombined with another compound of formula (I) or (I′).

Although the present invention focuses on the use of the presentcompounds for preventing or treating HIV infections, the presentcompounds may also be used as inhibitory agents for other viruses whichdepend on similar reverse transcriptases for obligatory events in theirlife cycle.

The following examples are intended to illustrate the present invention.Hereinafter, THF means tetrahydrofuran and DMF meansN,N-dimethylformamide.

Experimental Part

As described hereinbelow, DMF stands for N,N-dimethylformamide; THFstands for tetrahydrofuran; HPLC stands for High Performance LiquidChromatography.

Preparation of the Intermediate Compounds

EXAMPLE A1

a) Reaction under argon flow. A mixture of 4-aminobenzonitrile (0.0210mol) and diphenyl N-cyano-carbonimidate (0.0210 mol) in DMF (25 ml) wasstirred for 20 hours at 110° C. Water was added and the resultingprecipitate was filtered off, to give a brownish solid. This fractionwas recrystallized from CH₃CN. The precipitate was filtered off anddried. Yield: 1.67 g of phenyl N′-cyano-N-(4-cyanophenyl)-carbamimidate(interm. 1) (30%).

b) Reaction under argon flow. Intermediate (1) (0.00634 mol) was addedto a solution of 2,6-dichlorobenzeneethanimidamide (0.00634 mol) in DMF(13 ml). The reaction mixture was stirred for three days at roomtemperature, then for two days at 60° C. Water was added and theresulting precipitate was filtered off, to give a pure white solid. Thisfraction was refluxed in CH₃CN (500 ml), cooled and the precipitate wasfiltered off and dried. Yield: 1.58 g of4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile(interm. 2) (67%) (mp. 278-279° C.).

EXAMPLE A2

a) Preparation of Intermediate (3)

Reaction under argon atmosphere. 2,4,6-Trichloro-1,3,5-triazine (0.07440mol) and THF (100 ml) were combined and cooled to −75° C. Then,4-aminobenzonitrile (0.07440 mol) was added and the solution was stirredfor 4 hours. Then, N,N-diethylethanamine (0.07440 mol)) was addeddropwise and the reaction mixture was allowed to warm up slowly to roomtemperature and stirred for 3 days. After adding 1,4-dioxane (100 ml),the resulting precipitate was collected by filtration, washed with THF,and dried. Yield: 12.74 g of intermediate (3).

b) Preparation of Intermediate (9)

1.6 g (7.73 mmol) of 2-chloro-4-chloro-pyrimidine-6-carboxy methyl esterand 1.19 g (1.05 equiv.) of 4-hydroxy-3,5-dimethyl benzonitrile weredissolved in 20 ml of acetone and 1.28 g (1.2 equiv.) of K₂CO₃ and 58 mg(5 mol %) of NaI were added. The reaction was stirred at 20° C.overnight. After that the reaction mixture is cooled to 0° C. andfiltered off. Acetone is evaporated and the residue is dissolved inethyl acetate and washed with saturated aqueous NaHCO₃/H₂O 1/1. Theorganic layer was washed with brine, dried over Na₂SO₄ and evaporated.The residue was stirred in diisopropyl ether and the product wasfiltered off, the diisopropyl ether solution was cooled to 0° C. andmore product was filtered off and dried. Yield: 2.16 g of intermediate(9) (88%).

EXAMPLE A3

Preparation of Intermediate (4)

a) Ethanol (140 ml) was dried over sodium and distilled. Ethanol andsodium (0.0611 mol) were combined and stirred until homogeneous.N-(4-cyanophenyl)-guanidine monohydrochloride (0.05995 mol) and methyl4-methoxy-3-oxobutanoate (0.05995 mol) were added. The mixture wasstirred and refluxed for 5 hours and cooled to room temperature. Themixture was poured into a mixture of water (450 ml) and HOAc (50 ml).The mixture was stirred for 3 hours, filtered, washed with water, andair dried to produce 10.95 g white solid. The solid was dried at 95° C.overnight at 0.2 mm Hg. Yield: 10.19 g of intermediate (4) (66.4%)(264-265° C.).

b) Preparation of Intermediate (5)

Intermediate (4) (0.0234 mol) was stirred and refluxed in POCl₃ (30 ml)for 20 minutes. The mixture was poured onto ice and filtered to yield10.09 g off-white solid. The sample was dried at 80° C. for 16 hours at0.2 mm Hg. Yield: 6.27 g of intermediate (5) (97.6%) (174-176° C.).

EXAMPLE A4

Preparation of Intermediate (6)

2,4-Dichloro-6-[(2,6-dichlorophenyl)methyl]pyrimidine (2 mmol),1H-tetrazole (2 mmol), N,N-dimethylacetamide (20 ml) and K₂CO₃ (3.6 mol)were combined. The reaction mixture was stirred at 5° C. for 2 days. Themixture was poured to 5% HCl (50 ml) and then to ethyl acetate (50 ml).The layers were separated. The organic layer was extracted with brine(50 ml), dried over sodium sulfate, filtered, and the filtrate wasconcentrated. The product was purified by gradient elution from Silicagel 60 column (0-20% ethyl acetate in hexane). The desired fractionswere collected and the solvent was evaporated. White solid wasrecrystallized from ethanol. Yield: 0.15 g of intermediate (6) (mp.:167-169° C.).

EXAMPLE A5

Preparation of intermediate (7)

Hydrazinecarboxamide hydrochloride (0.0013 mol) was dissolved in boilingEtOH (50 ml), then was added NaOH (0.0013 mol), pyridine (0.0013 mol)and compound (1) (0.0013 mol). The mixture was refluxed for 6 hours.White solid obtained was separated via suction, brought in boilingmethanol and dioxane and dried. Yield: 0.48 g of intermediate (7) (mp.:149.5-252° C.).

EXAMPLE A6

Preparation of Intermediate (8)

2,5-Furandione (3 mmol) was added to the solution of4-[[4-[(2,6-dichlorophenyl)methyl]-6-hydrazino-1,3,5-triazin-2-yl]amino]benzonitrile(A) (2 mmol) in THF (40 ml). The THF solution was stirred for about 2hours at room temperature. The 100% conversion of (A) to intermediate(8) was confirmed by HPLC. Then THF was removed in vacuum. The rawproduct was added to absolute ethanol (30 ml) and this heterogenousmixture was refluxed for about 5 minutes. The solid was filtered off,washed with hot chloroform (ca. 20 ml) and dried. Yield: 0.6 g ofintermediate (8) (mp.: 229-231° C.).

EXAMPLE A7

a) Preparation of Intermediate (10)

Phosphor(isothiocyanatidic) acid, diphenyl ester (0.155 mol) was stirredin CH₂Cl₂ (300 ml). 3-(trifluoromethyl)-benzenamine (0.155 mol) wasadded dropwise and the reaction mixture was stirred overnight at roomtemperature. The mixture was poured out into water and this mixture wasstirred for 15 minutes. The layers were separated. The organic layer waswashed with water, dried, filtered and the solvent was evaporated. Theresidue was triturated under diisopropyl ether, filtered off and dried.Yield: 45 g of interm. (10) (64%).

b) Preparation of Intermediate (11)

A mixture of interm. (10) (0.0995 mol) and K₂CO₃ (0.4 mol) in2-propanone (500 ml) was stirred at room temperature. Diiodo-methane(0.2 mol) was added and the reaction mixture was stirred overnight. Themixture was filtered and the filtrate was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH99/10. The product fractions were collected and the solvent wasevaporated. Yield: 42.3 g of interm. (11) (91.6%).

c) Preparation of Intermediate (12)

A mixture of interm. (11) (0.069 mol) in HCl 36% (300 ml) and dioxane(300 ml) was stirred overnight at 40° C. and the solvent was evaporated.The residue was triturated under CH₃CN, filtered off and dried. Yield:13.8 g of interm. (12) (86.2%).

Preparation of the Final Compounds

EXAMPLE B1

a-1) 2,4-Dichloro-6-[(2,6-dichlorophenyl)methyl]-1,3-5-triazine (0.71mol) was stirred in toluene (2200 ml) to obtain white suspension (I).N-ethyl-N-(1-methylethyl)-2-propanamine (124 ml) was added to asuspension of 4-aminobenzonitrile (0.71 mol) in THF (2200 ml), givingsolution (II). Solution (II) was added dropwise to (I) over 105 minutesat 24-28° C. (water bath). The resulting reaction mixture was stirredovernight at room temperature. Water (2 liter) was added. The separatedorganic layer was washed twice with water (1.5 liter), and part of thesolvent was evaporated. The product crystallized out, was filtered offand dried (vacuum, 40° C., 20 hours). Yield: 235.4 g of4-[[4-chloro-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]-benzonitrile(85%) (compound 1) (243-244° C.).

a-2) Preparation of Compound 69

Reaction under argon flow. N-ethyl-N-(1-methylethyl)-2-propanamine(0.00714 mol) was added to a solution of 2-chloro-6-methylbenzenamine(0.00714 mol) in 1,4-dioxane (20 ml). A solution of intermediate (3)(0.00714 mol) in 1,4-dioxane (5 ml) was added. The reaction mixture wasstirred and refluxed for 24 hours. The solvent was evaporated. CH₂Cl₂was added. The organic layer was washed with a saturated aqueous NaHCO₃solution, and the resulting precipitate was filtered off. Yield: 0.56 gof compound 69 (21.1%, white solid).

a-3) Preparation of Compound 70

N-ethyl-N-(1-methylethyl)-2-propanamine (0.00752 mol) was added tointermediate (3) (0.00752 mol) in 1,4-dioxane (150 ml), under Argon.2,6-Dichlorobenzenethiol (0.00752 mol) was added to this mixture, whichwas then stirred at room temperature for 16 hours. The solvent wasevaporated, and the residue was dissolved in ethyl acetate, washed withNaHCO₃ and brine, then dried over Na₂SO₄, filtered and the filtrate wasevaporated. This fraction was recrystallized from CH₃CN (250 ml). Thefiltrate from recrystallization was concentrated to approximately 50 ml,cooled, and filtered. Yield: 0.85 g of compound 70 (28%, white solid,used in next reaction step, without further purification) (268-269° C.).

a-4) Preparation of Compound 24

In a flask of 25 ml with magnetic stirring and cooling

(1.9 mmol) and bromoaniline (4.74 mmol) (2.5 eq.) were added in ethanol(5 ml). The mixture was refluxed for 24 hours. The solvent wasevaporated. The residu was dissolved in 5 ml ether and 5 ml H₂O. Thelayers were separated. The aqueous layer was washed 3 times with ether.The organic layers were dried over Na₂SO₄. Yield: 1.2 g of compound 24.b) Reaction under argon atmosphere. A small portion of2-(bromomethyl)-1,3-dichloro-benzene in diethylether (40 ml) was addedto Mg (0.0813 mol) in diethylether (80 ml). Once the Grignard started toform, the solution of 2-(bromomethyl)-1,3-dichloro-benzene (0.0813 mol)in diethylether (40 ml) was added at a rate that kept the solutionrefluxing. The solution was stirred at room temperature for 2 hours and,then, added to a solution of 2,4,6-trichloro-1,3,5-triazine (0.0531 mol)in benzene (80 ml) at 0° C. The resulting solution was stirred at 0° C.for 1 hour and, then, at room temperature for 2 hours followed by theaddition of 4-aminobenzonitrile (0.0542 mol) in 1,4-dioxane (100 ml).The reaction mixture was stirred at room temperature for 16 hours. Then,N,N-diethylethanamine (0.0542 mol) was added, and the reaction mixturewas stirred further at room temperature. The reaction mixture wasquenched with H₂O, extracted with ethyl acetate, washed with brine (3×),and dried over K₂CO₃, filtered and the solvent was evaporated. Theresidue was treated with CH₂Cl₂ and the resulting precipitate wascollected by filtration. Yield: 6.99 g of fraction 1 (an off-whitesolid). The collection of precipitate from subsequent filtrationsyielded: 1.80 g of fraction 2 and 1.30 g of fraction 3. Fraction 3 waspurified by flash column chromatography over silica gel (eluent:CH₂Cl₂). The desired fractions were collected and the solvent wasevaporated. The residue was treated with CH₂Cl₂, filtered off and dried.Yield: 1.47 g of fraction 4.

Fractions 1, 2 and 4 were combined and treated with CH₃CN (600 ml). Thesolvent was evaporated and the residue was dried under vacuum at 80° C.and 2.0 mm Hg for 16 hours. The residue was treated with CH₃CN (300 ml),filtered off and dried (2×). The product was dried under vacuum at 100°C. and 0.2 mm Hg for 16 hours. Yield: 2.87 g of4-[[4-chloro-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]-benzonitrile(14.3%); (compound 1) (mp.: 243-244° C.).

c) Preparation of Compound 71

Intermediate (9)

(prepared according to A2b)) (0.00737 mol), 4-aminobenzonitrile (0.01511mol), and 1-methyl-2-pyrrolidinone (5 ml) were added to a pressurevessel under argon. The mixture was heated at 125-130° C. for 7 hours,and the heat was removed. Water, then ether were added. The mixture wasstirred and filtered. The filtrate was stirred for 6 hours, andfiltered. The filtrate was filtered again. This filtrate was evaporated,then extracted with CH₂Cl₂. This sample was purified by preparative HPLC(gradient of 0.1% trifluoroacetic acid in water and 0.1% trifluoroaceticacid in CH₃CN). Yield: 0.20 g of compound 71 (white powder) (mp.:258-259° C.).d) Preparation of Compound 39

To a solution of

,4-aminobenzonitrile and 2-methyl-2-propanol in dry dioxane was addedcatalysator Pd(PPh₃)₄. The solution was heated to 100° C. with stirringuntil2-chloro-4-[(2,6-dichlorophenyl)methyl]-6-(1-imidazolyl)-pyrimidine hadbeen completely consumed. The solution was then cooled to roomtemperature, taken up in ether (30 ml), and washed with brine (15 ml).The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The crude product was then suspended in 15% HCl and thesolid was filtered off. The crude product was purified by gradientelution from Silica gel 60 column (0-25% acetone in hexane). Yield:compound 39 (mp.: 275-285° C.).e) Preparation of Compound 43

Compound 1 (0.001 mol) and O-2-propenyl-hydroxylamine (0.0022 mol) weredissolved in 1,4-dioxane (3 ml) in a sealable tube, and NaOH 3M (0.002mol) was added. The tube was flushed with argon, sealed, and heated for2 hours to 95° C., and cooled to room temperature. The solvent wasevaporated at 60° C. under a strong nitrogen flow, and the residue waspurified by reverse phase HPLC. The product fractions were collected andthe solvent was evaporated. Yield: 0.330 g of compound 43 (77.3%, whitesolid) (mp.: 225-227° C.).

EXAMPLE B2

a) Preparation of Compound 2

NaH (0.00120 mol) was added to a solution of intermediate (5) (0.00109mol), 4-hydroxy-3,5-dimethylbenzonitrile (0.00120 mol), 1,4-dioxane (15ml) and 1-methyl-2-pyrrolidinone (15 ml) in a flask under argon. Afterthe gas evolution ceased, the reaction was heated in an oil bath at135-140° C. for 16 hours. The solvent was evaporated, acetonitrileadded, the precipitate filtered and washed with cold CH₃CN to give 3.95g of fraction 1. The filtrate was filtered to give 0.46 g of fraction 2.The solids were combined and chromatographed on silica gel eluting with0 and 1% methanol:methylene chloride to give 3.25 g of white solid. Thissolid was stirred in refluxing CH₃CN and filtered to give 2.56 g ofcompound (2) (mp.: 203-204° C.).

b) Preparation of Compound 72

A solution of 2,4,6-trichlorophenol (0.0075 mol) in dry THF (35 ml) wasadded dropwise over 30 minutes. to a suspension of cleaned NaH (0.0075mol) in dry THF (5 ml). After 30 minutes of stirring (someeffervescence), the mixture was a clear solution, and intermediate (3)(0.0076 mol) was added in one portion followed by additional THF (40ml). The heterogeneous mixture was stirred over the weekend. More NaH(0.09 g) was added in one portion and the reaction mixture was stirredfor 18 hours. The reaction was quenched by pouring into 250 ml of ice. Aprecipitate formed. The sample and filtrate were treated with ethylacetate and the layers were separated. The aqueous pH was adjusted with1 M NaOH and re-extraction was performed. The basic aqueous fraction wasthen extracted further with ethyl acetate and the combined organicfractions were dried (MgSO₄), filtered and the solvent was evaporated invacuo. The residue was purified by flash column chromatography oversilica gel (eluent: 100% CH₂Cl₂). Two pure fraction groups werecollected. The appropriate di-addition fractions were combined to afford0.28 g of off-white solid which was triturated under diethyl ether, thendried. The appropriate mono-addition fractions were combined and, whenneeded, recrystallized from ethyl acetate. The obtained residue waspurified by chromatography. Yield: 1.28 g of compound 72 (mp.: 238-239°C.).

c) Preparation of Compound 60

NaOH (0.0036 mol) was added to a solution of4-hydroxy-3,5-dimethylbenzonitrile in acetone (3.6 ml). The product

was suspended in acetone/H₂O (50 ml). The solution of4-hydroxy-3,5-dimethylbenzonitrile was added to the suspension and mixedovernight at laboratory temperature. The reaction mixture was dilutedwith water to 100 ml and neutralised by acetic acid. The crude productwas separated by filtration, dried in air and crystallised fromchloroform. Yield: 1.04 g (92%) of compound 60 (mp. 260-265° C.).

EXAMPLE B3

Preparation of Compound 3

Reaction in a pressure flask under argon. A mixture of intermediate (5)(0.00364 mol), 2-chloro-4-fluoro-5-methylbenzenamine (0.00401 mol),N-ethyl-N-(1-methylethyl)-2-propanamine (0.00401 mol) and1-methyl-2-pyrrolidinone (2 ml) in 1,4-dioxane (3 ml) was heated in anoil bath at 140° C. for 3 days. The heat was increased to 160-165° C.,and the mixture was heated for 2 days. The heat was increased to180-185° C., and the mixture was heated for 4 days. The mixture waspoured into H₂O, extracted (Et₂O), washed with brine, dried (Na₂SO₄),and evaporated to produce 1.55 g of pale yellow solid. The solid wassonicated in CH₂Cl₂, filtered and recrystallized from CH₃CN to yield0.32 g of compound (3) (22.1%) (mp.: 213-214° C.).

EXAMPLE B4

Preparation of Compound 4

1,4-Dioxane-2,6-dione (0.067 mol) and4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile(0.00135 mol) were added to a flask and heated in an oil bath whilestirring to give a clear solution. The reaction reached 165° C. in 15minutes, and was maintained at 165° C. for 35 minutes. The reactionmixture was then removed from the oil bath, cooled to room temperature,then treated between cold water and diethyl ether, using sonication tobreak up all of the solid mass. The mixture was transferred to aseparatory funnel, which gave a quantity of insoluble material. Themixture was suction filtered (collected 0.33 g of white powder) and thefiltrate was returned to the funnel. The Et₂O was washed with distilledwater until the pH was brought from about 3.0 to neutrality. The mixturewas dried over Na₂SO₄ to yield 0.24 g of fluffy white wax from theextraction. All material was recombined and purified by flash columnchromatography with a solvent coated onto the silica gel usingCH₂Cl₂/CH₃CN and a forerun of 250 ml of CH₂Cl₂. The solvent was changedto 95:5 CH₂Cl₂/Et₂O, then 90:10. The desired fractions were collectedand the solvent was evaporated. The residue was recrystallized oncemore. Yield: 0.090 g of compound (4) (14.2%) (mp.: 268-269° C.).

EXAMPLE B5

a) Preparation of Compound 5

A mixture of compound (1) (0.00768 mol), NaCN (0.00971 mol) andPd(PPh₃)₄ (0.0247 mol) in N,N-dimethylacetamide (200 ml, freshlydistilled) was stirred for 40 minutes at 120° C. The reaction mixturewas cooled, poured out into ice-cold water and the resulting precipitatewas filtered off, washed with water and dried (vacuum). Some impuritieswere then removed by double extraction with diethyl ether. This fraction(2.70 g) was purified by column chromatography over silica gel (eluent:CH₂Cl₂/(CH₃OH/NH₃ satd.) from 100/0 to 90/10). The desired fractionswere collected and the solvent was evaporated. Yield: 1.7 g of compound(5) (mp.: 221-230° C.).

b) Preparation of Compound 40

Compound 5 (prepared according to B5a)) was suspended in HCOOH (25 ml)with stirring on a magnetic stirrer. A stream of gas HCL was then passedthrough the reaction mixture for 1 hour. The mixture was stirred for 20hours. A product was precipitated by pouring of the reaction mixtureinto water. Precipitated solid was then filtered off, washed with waterand dried in vacuum dryer. Yield: 4.10 g (89.3%) of compound 40 (mp.:287-295° C.).

c) Preparation of Compound 42

Compound 5 (prepared according to B5a)) (0.0015 mol), NaN₃ (0.030 mol),NH₄Cl (0.030 mol) and N,N-dimethylacetoacetamide (15 ml) were combined.The reaction mixture was stirred at 140° C. for 2 hours. The mixture waspoured into 150 ml 5% HCl. The crude product was filtered off, washedwith cold water and dried. The product was recrystallized from glacialacetic acid. Yield: 0.67 g (96%) of compound 42 (mp.: 249-252° C.).

d) Preparation of Compound 38

Compound 5 (prepared according B5a)) (5.24 mmol) was suspended in HCOOH(15 ml) with stirring on magnetic stirrer. A stream of gas HCl was thenpassed through the reaction mixture. The mixture was poured into waterafter 45 minutes. Precipitated solid was then filtered off, washed withwater and dried in vacuum dryer. The crude product (1.91 g) wasrecrystallized from acetonitrile. Yield: 1.53 g (73.1%) of compound 38(mp.: 262-263° C.).

e) Preparation of Compound 33

In a flask of 25 ml equipped with magnetic stirring and cooling compound32 (prepared according to B1c)) (0.47 mmol) and CuCN (2 eq.) were pouredinto 1-methyl-2-pyrrolidinone (1 ml). The reaction mixture was heated at150° C. overnight (18 hours.). After cooling, the mixture was dilutedwith cold H₂O (8 ml) and placed into an icebath for 30 minutes. Theprecipitate was filtered and washed with ether, carefully triturated andagain filtered. Yield: 208 mg of compound 33 (mp.: 249-251° C.).

EXAMPLE B6

Preparation of Compound 6

Reaction under argon atmosphere. Sodium sulfide (0.01024 mol) was addedto compound (1) (0.00512 mol) in 1,4-dioxane (100 ml). The reactionmixture was stirred at room temperature for three days and the solventwas evaporated. The residue was dissolved in ethyl acetate, washed with1 N HCl (30 ml), a saturated aqueous sodium bicarbonate solution andwith brine, dried with sodium sulfate, filtered, and the solvent wasevaporated to give 2.49 g of white solid. This fraction wasrecrystallized once from acetonitrile to give 0.58 g of fraction 1.

The filtrate was concentrated. The concentrate was cooled and filteredto give 0.59 g of fraction 2. Fractions 1 and 2 were combined andpurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH100/0, 99/1 and 98/2). The pure fractions were collected and the solventwas evaporated. The residue was recrystallized from acetonitrile. Theprecipitate was filtered off and dried (0.2 mm Hg, 80° C., 16 hours).Yield: 0.76 g of compound (6) (38.3%) (mp. 254-255° C.).

EXAMPLE B7

a) Preparation of Compound 7

Reaction under argon atmosphere. A mixture of compound (1) (0.00256 mol)and NaSCH₃ (0.00269 mol) in dimethylsulfoxide (10 ml) was stirred for 16hours at room temperature. Water was added and this mixture wasextracted with ethyl acetate. The separated organic layer was washedwith brine, dried with potassium carbonate, filtered, and the solventwas evaporated. The residue was crystallized from methanol, thenrecrystallized from acetonitrile. The sample was dried at 80° C., 0.2 mmHg for 16 hours. Yield: 0.70 g of compound (7) (68.0%) (mp. 184-185°C.).

b) Preparation of Compound 8

Reaction under argon atmosphere. 3-Chlorobenzenecarboperoxoic acid(0.00373 mol) was added to a solution of compound (7) (0.00249 mol) inethanol (150 ml). The reaction mixture was stirred at room temperaturefor 40 minutes, poured into 600 ml of ice water, extracted two timeswith ethyl acetate, washed with brine, dried with potassium carbonate,filtered and the solvent was evaporated to give an off-white solid. Thesolid was stirred in 2% methanol:methylene chloride (50 ml) andfiltered. The filtrate was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH 100/0, 99/1 and 98/2). The desired fractionswere collected and the solvent was evaporated to give 0.39 g of product.This fraction was recrystallized from methanol. The precipitate wasfiltered off and dried. The sample was dried at 80° C., 0.2 mm Hg for 16hours. Yield: 0.20 g of compound (8) (19.2%) (mp. 219-221° C.).

EXAMPLE B8

Preparation of Compound 9

A suspension of compound (1) (0.0205 mol) in methanol (20 ml) wastreated with LiOCH₃ (0.0021 mol) in one portion and the heterogeneousreaction mixture was stirred vigorously at room temperature for 28hours. The reaction mixture was diluted with ether and treated with icecold 1 M HCl. The layers were separated and the acidic aqueous phase wasextracted four more times with ether. The combined ether layers weredried over MgSO₄/Na₂SO₄, filtered and the filtrate was evaporated. Theresidue was recrystallized twice from acetonitrile. The precipitate wasfiltered off and dried. Yield: 0.43 g of compound (9) (54.3%) (mp.198-199° C.).

EXAMPLE B9

Preparation of Compound 10

Sodium acetate (0.00463 mol) was added to a solution of compound (1)(0.00153 mol) in dimethylfsulfoxide (15 ml) and the mixture was-stirredfor 72 hours at room temperature. The reaction mixture was poured into a100 ml ice-water slurry which caused a voluminous precipitate to form;the mixture was placed in the refrigerator overnight. The precipitatewas filtered off, washed extensively with cold water, then dried to give1.17 g of white solid. This material was powdered and then trituratedwith ether to give 0.53 g of white powder. One half (0.26 g) of thismaterial was dissolved in pyridine (5 ml) and treated with acetylchloride (0.07 ml, 0.00098 mol) in one portion. The reaction mixture wasstirred at room temperature for 72 hours, then concentrated in vacuo,and extracted between CH₂Cl₂ and a saturated aqueous NaHCO₃ solution. Avoluminous solid was insoluble in either fraction. The triphasic mixturewas suction filtered and the collected solid was washed extensively withwater, then air-dried. Yield: 0.19 g of compound (10) (mp. >300° C.).

EXAMPLE B10

a) Preparation of Compound 11

Compound (1) (0.00075 mol) and 4-isoxazolidinol HCl (0.0008 mol) weredissolved in 1,4-dioxane (3 ml) in a sealable tube, and NaOH 3M (0.0018mol) was added. The tube was flushed with nitrogen, sealed, and heatedfor 3 hours to 90° C., and cooled to room temperature. Methylenechloride (5 ml) and methanol (2 ml) were added, the tube was shakenvigorously, and the bottom (aqueous) layer was removed with a pipette.The organic layer was dried over potassium carbonate, and the tube wascentrifuged. The supernatant was separated and evaporated at 50° C.under a steady nitrogen flow. The residue was purified by reverse phaseHPLC. The pure fractions were collected and the solvent was evaporated.Yield: 0.160 g of compound (11) (49.7%) (mp. 175° C.).

b) Preparation of Compound 46

Compound 1 (0.002 mol), 1H-tetrazol-5-amine (0.004 mol),N,N-dimethylacetamide (6 ml) and K₂CO₃ (0.004 mol) were combined. Thereaction mixture was stirred at 120° C. for 60 minutes. Mixture waspoured into cold water. A product was filtered off, washed with hotwater and dried. The product was crystallized from the mixture oftetrahydrofurane/n-heptane. Yield: 0.79 g (90%) of compound 46 (mp.:302-304° C.).

EXAMPLE B11

a) Preparation of Compound 12

Br₂ (0.12523 mol) was added to a solution of compound (2) (0.00475 mol)and THF (55 ml). After 9 hours, N,N-diethylethanamine (1.32 ml), Br₂(0.22 ml), THF (10 ml), and water (10 ml) were added, and thehomogeneous clear solution was stirred overnight. Water (100 ml) wasadded, and the mixture was extracted (ether), washed (water, brine), anddried (K₂CO₃). The aqueous phase was washed (ether). The ether phase waswashed (brine). The organic phases were combined and evaporated toproduce 3.75 g white solid. The solid was recrystallized in CH₃CN, driedat 80° C. for 16 hours at 0.2 mm Hg to yield 2.19 g of compound (12)(89%) (mp. 198-199° C.).

b) Preparation of Compound 13

BBr₃ in CH₂Cl₂ (0.01825 mol) was added dropwise over 5 minutes tocompound (12) (0.00332 mol) in CH₂Cl₂ (16 ml) under argon at −78° C. ina dry ice/2-propanol bath. The mixture was stirred at −78° C. for 20minutes. The bath was replaced with an ice water bath, and the mixturewas stirred at 0° C. for 50 minutes. Water and CH₂Cl₂ were added untilthe solution became homogeneous. The organic phase was separated anddried (K₂CO₃). Column chromatography through short path of silica gel(eluent 5% methanol: CH₂Cl₂) produced 1.71 g off-white solid. The solidwas taken up in CH₂Cl₂, washed (NaHCO₃), dried (Na₂SO₄), and evaporated.The residue was recrystallized in 2-propanol (250 ml) to yield 1.14 g ofcompound (13) (71.7%) (279-281° C.). The solid was dried at 80° C. for 4hours at 0.2 mm Hg.

c) Preparation of Compound 73

SOCl₂ (0.00157 mole) was added to THF (7 ml) and cooled in an ice bathunder argon. Compound 13 (prepared according to B11b)) (0.0013 mole) andN,N-diethylethanamine (0.0013 mole) were added in THF (10 ml). Thereaction was stirred until the ice melted, and the reaction returned toroom temperature. SOCl₂ (0.100 ml) was added at room temperature, andthe reaction was stirred for 2 hours. More SOCl₂ (0.05 ml) was added,and the reaction was stirred for 1.5 hours. The mixture was filtered andthe white solid was rinsed with THF. The filtrate was evaporated. Yield0.600 g of compound 73 (97.9%, light yellow solid) (mp.: 238-240° C.).

d) Preparation of Compound 74

Compound 73 (prepared according to B11c)) (0.000416 mole) was dissolvedin methylamine (0.008 mol) in a closed flask and stirred at roomtemperature for 40 hours. The solvent and excess amine were evaporated.The resulting solid was taken up in ethyl acetate and washed withaqueous NaHCO₃ and brine. The organic layer was dried with sodiumsulfate and evaporated to give 0.123 g of a yellow solid. The materialwas recrystallized from ethanol (3×). The solid was dried under vacuumwith refluxing toluene overnight. Yield: 0.025 g of compound 74 (13%,yellow orange solid) (mp.: 223-224C.).

EXAMPLE B12

(compound 14) (prepared according to example B11b)), acetonitrile (10ml), and CHCl₃ (10 mL) was added 1,4-Diazoniabicyclo[2.2.2]octane,1-(chloromethyl)-4-fluoro-, bis[tetrafluoroborate(1-)] (0.000639 mol).The reaction mixture was refluxed for 15.5 hours, evaporated, dissolvedin methylene chloride, washed with water, filtered, dried with potassiumcarbonate and evaporated. Chromatography on the Gilson Prep LC gave0.0017 g of compound (15) (0.5%) (240-241° C.) and 0.0097 g of compound(16) (2.6%) (m.p.: 250-251° C.).

EXAMPLE B13

Preparation of Compound 37

Pentanedioyl dichloride (24 mmol) was added (in portions) to the stirredand refluxed solution of intermediate (2) (6.4 mmol) in dioxane (100ml). The conversion of intermediate (2) to compound (37) was monitoredby HPLC. The reaction mixture was filtered and dioxane was removed invacuum. The residue obtained was washed with methanol (50 ml) andcollected by suction. This solid was purified by slow crystallizationfrom methanol (1000 ml). Yield: 1.09 g (36.5%) of compound (37) (mp.278-282° C.).

EXAMPLE B14

Preparation of Compound 36

(interm. 8) (2.5 mmol) was added to the suspension of sodium acetate(0.3 g) in acetic acid anhydride (12 ml). The mixture was stirred for 30minutes at 55° C. The reaction was monitored by HPLC. The reactionmixture was poured into a solution of methanol (8 ml) and stirred for 20minutes. Precipitated solid was collected by suction, washed withmethanol (3 ml) and dried. The raw product was extracted with CHCl₃ (70ml). The CHCl₃ solution was filtered and concentrated by destillation.Heptane (30 ml) was added to the concentrated CHCl₃ solution (20 ml).The precipitated solid was collected by suction and dried. This solidwas finally purified by washing with hot methanol (2×10 ml) and hotacetone (1×3 ml). The solid was collected by suction and dried. Yield:0.18 g (16%) of compound 36.

EXAMPLE B15

Preparation of Compound 49

Compound 1 (0.00512 mol) was dissolved in sulfolane (90 ml)(dried,destilled). KF (0.01455 mol) (freshly burnt) was added at 90° C.Reaction was monitored by HPLC analysis. After 8.5 hours the mixture wascooled to laboratory temperature and poured under good mixing into 500ml of destined water. The precipitate was filtered off and mixed with500 ml of water and the suspension was sonificated and filtered. Thisprocedure was repeated once more. Finally the solid was washed with 150ml water and dried in the vacuum dryer at 70° C. Yield: 1.87 g ofcompound 49 (white solid) (mp.: 199-201° C.).

EXAMPLE B16

a) Preparation of Compound 62

1.00 gram (2.67 mmol) of2-N-(4-cyanoaniline)-4-N-(2,4,6-trimethylaniline)pyrimidine-6-carboxylicacid was dissolved in 10 ml of MeOH and 1.13 ml (5 equiv.) ofdimethylcarbonate and 40 drops of concentrated H₂SO₄ were added. Thereaction mixture was stirred at 65° C. for 1 week. After that thereaction was quenched with aqueous saturated NaHCO₃ and the MeOH wasevaproated. The product was extracted with ethyl acetate and the extractwas washed with brine, dried over Na₂SO₄ and evaporated. The residue waspurified by column chromatography (SiO₂/ethyl acetate) to afford 579 mg(56%) of compound 62.

b) Preparation of Compound 61

80 mg (0.206 mmol) of compound 62 (prepared according to B16a)) wasdissolved in 1.5 ml of dry THF and 1.5 ml of a 7N methanolic solution ofNH₃ was added. The mixture was stirred at 20° C. overnight. After thatthe product was filtered off, washed with THF and dried to yield 74 mg(96%) of compound 61.

c) Preparation of Compound 63

80 mg (0.197 mmol) of compound 62 (prepared according to B16a)) wasdissolved in 4 ml THF/MeOH 1/1 and 133 mg (10 eq.) of H₂NMe.HCl and 0.5ml (15 equiv.) of N,N-diisopropylethanamine were added. The reaction wasstirred overnight at 20° C. and after that, the solvents wereevaporated. The residue was taken up in ethyl acetate and washedsuccessively with 0.5 N aqueous KHSO₄ (2×) and with brine, dried overNa₂SO₄ and evaporated. The residue was stirred in n-heptane/diisopropylether 1/1 and the product was filtered off and dried to yield 60 mg(75%) of compound 63.

d) Preparation of Compound 66

50 mg (0.123 mmol) of compound 62 (prepared according to B16a)) wasdissolved in 3 ml of dry THF and 0.200 ml (1.25 equiv.) of

(0.76 M in hexane/toluene) was added. The mixture was stirred overnightat 20° C.; 0.050 ml of

was added and the mixture was stirred for another night. After that theTHF was evaporated and the residue was taken up in ethyl acetate andwashed successively with saturated aqueous NaHCO₃ and with brine, driedover Na₂SO₄ and evaporated. The residue was stirred inn-heptane/diisopropyl ether 1/1 and the product was filtered off anddried to yield 44 mg (85%) of compound 66.

EXAMPLE B17

Preparation of Compound 41

20 ml of solution C(═O)Cl₂ in dioxane (circa 20%) was warmed up to 75°C. Intermediate 7 (prepared according to A5) was added in small portionsin 4.5 hours. Content C(═O)Cl₂ was checked (aniline) in reaction mixtureand excess was maintained by addition of solution C(═O)Cl₂. Dioxane wasevaporated to dryness and yellow solid was treated with acetone. Whitesolid obtained was filtered and recrystallized from methanol. Yield:0.87 g (39.3%) of compound 41 (mp.: 192-195° C.).

EXAMPLE B18

Preparation of Compound 35

The mixture of4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitrile(9mmol) and THF (50 ml) was stirred and cooled (−12° C.). ClCH₂CH₂C(═O)Cl(10.5 mmol) in THF (15 ml) was added dropwise into the previouslyprepared mixture for about 15 minutes. The solvent was removed bydestination under reduced pressure. The part of raw product waschromatographed on silica gel (CH₂Cl₂/acetone 95:5). The obtained solidwas recrystallized from mixture chloroform-heptane (25% chloroform).Yield: 0.1 g (2.5%, white solid) of compound 35 (mp.: 168-173° C.).

EXAMPLE B19

Preparation of Compound 34

The mixture of compound 47 (prepared according to B14) (0.4 mmol) inmethanol (50 ml) was refluxed and stirred for 5.5 hours. The conversionof compound 47 to compound 34 was monitored by HPLC. The reactionmixture was concentrated by destillation. The precipitated solid wascollected by suction and dried. Yield: 102 mg (55%, white solid) ofcompound 34 (mp.: 155-157° C.).

EXAMPLE B20

a) Preparation of Compound 52

500 mg (1.57 mmol) of interm. (9), 586 mg (3 equiv.) of5-amino-2-methoxy-pyridine and 47 mg (0.2 mol %) of Nal were dissolvedin 10 ml of 1,2-dimethoxy-ethane and stirred at 60° C. for 3 days. Then,the mixture was diluted with ethyl acetate and washed succesively with0.5 N aqueous KHSO₄ (2×) and with brine. The organic layer was driedover Na₂SO₄ and evaporated. The residue was purified by silica columnchromatography using ethyl acetate/n-heptane 1/1 as the eluent to obtain306 mg (48%) of compound 52.

b) Preparation of Compound 56

100 mg (0.247 mmol) of compound 52 was dissolved in 2.5 ml of THF andcooled to 0° C. 2.5 ml of a 7 N methanolic NH3 solution was added. Themixture was stirred overnight in a cooler at ±4° C. The reaction mixturewas diluted with diisopropyl ether and evaporated. More diisopropylether was added and the mixture was cooled. The product was filtered offto yield 93 mg (96%) of compound 56.

c) Preparation of Compound 54

80 mg (o,197 mmol) of compound 52, 133 mg (10 equiv.) of H₂NMe.HCl and0.5 ml (15 equiv.) of N,N-diisopropylethanamine were dissolved in 4 mlTHF/MeOH 1/1 and stirred overnight at 20° C. After that, the solventswere evaporated and the residue was dissolved in ethyl acetate andwashed succesively with 0.5 N KHSO₄ (2×) and brine, dried over Na₂SO₄and evaporated. The residue was stirred in n-heptane/diisopropyl ether1/1 and the product was filtered off and dried to yield 60 mg (75%) ofcompound 54.

d) Preparation of Compound 65

50 mg (o. 123 mmol) of compound 52 was dissolved in 3 ml of dry THF and200 μl (1.25 equiv.) of

(0.76 M in hexane/toluene) was added. The mixture was stirred overnightat 20° C. 50 μl of

was added and stirring was continued for another night. Then, THF wasevaporated and the residue was taken up in ethyl acetate and washedsuccessively with saturated aqueous NaHCO₃ and with brine, dried overNa₂SO₄ and evaporated. The residue was stirred in n-heptane/diisopropylether 1/1 and the product was filtered off and dried to yield 44 mg(85%) of compound 65.e) Preparation of Compound 95

31 mg (o.o765 mmol) of compound 52 was dissolved in 0.73 ml of 0.1 Nsolution of Br₂ in acetic acid (0.95 equiv.). After overnight stirringat 20° C., the solvent was evaporated and the residue was stirred inethyl acetate/saturated aqueous NaHCO₃ until gas evolution ceased. Theorganic layer was washed with brine, dried over Na₂SO₄ and evaporated.The residue was purified by silica preparative thin layer chromatographyusing ethyl acetate/n-heptane 1/4 as the eluent. The major band isscraped off the thin layer chromatography plate and extracted. Theextract was evaporated and dried to yield 21 mg (58%) of compound 95.

f) Preparation of Compound 55

20 mg (0.0494 mmol) of compound 52 was suspended in 2 ml of H₂O and 23mg (3 equiv.) of Br₂ were added. The mixture was stirred at 60° C.overnight. Then, the mixture was cooled to 20° C. and filtered off. Theresidue was purified by silica preparative thin layer chromatographyusing ethyl acetate/n-heptane 1/2 as the eluent. The major band isscraped off the thin layer chromatography plate and extracted. Theextract was evaporated and dried to yield 10 mg (36%) of compound 55.

g) Preparation of Compound 53

100 mg (0.247 mmol) of compound 52 was dissolved in 7.5 ml of MeOH and1.75 ml of a 0.4 N aqueous LiOH solution was added. The mixture wasstirred at 20° C. for 4 hours. Then, Amberlite ion exchange material(H⁺-form) was added and 2 ml of MeOH. When the solution was neutral, theAmberlite was filtered off, MeOH was evaporated and the residue wasstirred in diisopropyl ether, filtered off and dried to yield 80 mg(83%) of compound 53.

EXAMPLE B21

a) Preparation of Compound 50

200 mg (0.654 mmol) of2-chloro-4-N-(2,4,6-trimethylanilinyl)-pyrimidine-6-carboxy methylester, prepared according to A2a), and 244 mg (3 equiv.) of5-amino-2-methoxy-pyridine were dissolved in 2 ml of n-BuOH and 2 ml ofH₂O and 3 drops of 37% aqueous HCl were added. The reaction mixture wasstirred at 85° C. for 2 days. Then, the solvents were evaporated, theresidue was stirred in 15 ml H₂0/15 ml CH₂Cl₂ and the solid material wasfiltered off. The residue was washed with H₂O, with diethyl ether andwith CH₂Cl₂ to yield 127 mg (51%) of compound 50.

b) Preparation of Compound 51

60 mg (0.158 mmol) of compound 50 was suspended in dry DMF and 58 μl (5equiv.) of SOCl₂ were added. The reaction mixture was stirred at 60° C.overnight and the excess SOCl₂ was removed by evaporation. The DMFsolution was cooled to 0° C. and 2 ml of 37° C. NH₄OH was added. Thereaction mixture was stirred for 1 hour at 0° C. Then, the solvents wereevaporated and the residue was stirred in MeOH for 2 hours, filtered offand washed with diisopropyl ether to yield 30 mg (50%) of compound 51.

EXAMPLE B22

a) Preparation of Compound 96

60 mg (0.155 mmol) of compound 62, prepared according to B16a), wasdissolved in 1.7 ml of 0.1 N solution of Br₂ in acetic acid (1.1equiv.). After 1 hour, the solvent was evaporated and the residue wasstirred in ethyl acetate/saturated aqueous NaHCO₃ until gas evolutionceased. The organic layer was washed with brine, dried over Na₂SO₄ andevaporated. The residue was stripped with n-heptane and stirred inn-heptane/diisopropyl ether 1/1 and the product was filtered off anddried to yield 72 mg (100%) of compound 96.

b) Preparation of Compound 98

105 mg (0.225 mmol) of compound 96 was dissolved in 2 ml of MeOH and 2ml of a 7 N NH₃ solution in MeOH was added. The reaction was stirred at20° C. over the weekend. The solvent was evaporated and the residuestripped with CH₂Cl₂, stirred in diisopropyl ether and filtered off toyield 64 mg (63%) of compound 98.

EXAMPLE B23

Preparation of Compound 93

A mixture of interm. 12 (0.00028 mol) and benzeneacetyl chloride(0.00028 mol) in acetonitrile (10 ml) was stirred while cooling on anice-bath. Sodium acetate (0.00084 mol) was added and the mixture wasstirred for 30 minutes on an ice-bath, then stirred overnight at roomtemperature. Methyl carbamimidothioate (0.00056 mol) was added. Na₂CO₃(0.0011 mol) was added and the mixture was stirred overnight at 80° C.,then cooled to room temperature. CH₂Cl₂ (10 ml) was added. Water (2 ml)was added and the mixture was stirred for 30 minutes. The mixture wasfiltered through Extrelut and the filtrate was evaporated. The residuewas purified by HPLC over silica gel (eluent: CH₂Cl₂/CH₃OH 90/10). Theproduct fractions were collected and the solvent was evaporated to yieldcompound 93.

The following Tables list compounds of formula (I) as prepared accordingto one of the above examples (Ex. No.).

TABLE 1

Co. Ex. Physical No. No. Z R² L Q data/mp. 17 B1a-2 CH Br(2,4,6-trimethylphenyl)amino CF₃ 198–201° C. 18 B5a N CN(2,4,6-trimethylphenyl)amino CN 309–313° C. 19 B5d N CN(2,4,6-trimethylphenyl)amino C(═O)—NH₂ 20 B7 N CN(2,4,6-trimethylphenyl)aniino SCH₃ 108–109° C. 21 B5e CH CN(2,4,6-trimethylphenyl)amino CF₃ 179–182° C. 22 B21a CH CN(2,4,6-trimethylphenyl)amino COOH 23 B5a N CN (2,4,6-trimethylphenyl)oxyCN 24 B1a-4 CH Br (2,4,6-trimethylphenyl)oxy CF₃ 129° C. 25 B5e CH CN(2,4,6-trimethylphenyl)oxy CF₃ 202° C. 26 B5d N CN(2,4,6-trimethylphenyl)oxy C(═O)—NH₂ 280–286° C. 27 B2 CH CN(2,6-dibromo-4-cyano CH₂—O—CH₃ 218–220° C. phenyl)oxy 14 B12 CH CN(2,6-dibromo-4-cyano CH₂—OH 277–278° C. phenyl)oxy 15 B12 C—F CN(2,6-dibromo-4-cyano CH₂—OH 240–241° C. phenyl)oxy 16 B12 C—Br CN(2,6-dibromo-4-cyano CH₂—OH 250–251° C. phenyl)oxy 28 B5 N CN(4-cyano-2,6-dimethyl CN 288–291.5° C. phenyl)oxy 29 B5e CH CN(2,6-dimethylphenyl)amino CF₃ 30 B5e CH CN (2,6-dimethylphenyl)oxy CF₃31 B1a-4 CH Br (2,6-dimethylphenyl)oxy CF₃ 3 B3 CH CN(2-chloro-4-fluoro-5-methyl- CH₂—O—CH₃ 213–214° C. phenyl)amino 32 B1cCH CN (4-bromo-2,6-dimethyl- CF₃ 209–211° C. phenyl)amino 33 B5e CH CN(4-cyano-2,6-dimethyl- CF₃ 249–251° C. phenyl)amino 2 B2 CH CN(4-cyano-2,6-dimethyl CH₂—O—CH₃ 203–204° C. phenyl)oxy 12 B11a C—Br CN(4-cyano-2,6-dimethyl CH₂—O—CH₃ 198–199° C. phenyl)oxy 13 B11b C—Br CN(4-cyano-2,6-dimethyl CH₂—OH 279–281° C. phenyl)oxy 57 B2b N CN(2,4,6-trimethylphenyl)oxy Cl 234–236° C. 60 B2c N CN(4-cyano-2,6-dimethyl Cl 260–265° C. phenyl)oxy 61 B16b CH CN(2,4,6-trimethylphenyl)amino C(═O)—NH₂ 62 B16a CH CN(2,4,6-trimethylphenyl)amino C(═O)—OCH₃ 63 B16c CH CN(2,4,6-trimethylphenyl)amino C(═O)—NHCH₃ 66 B16d CH CN(2,4,6-trimethylphenyl)amino C(═O)—N(CH₃)₂ 67 B1a-2 N CN(2,4,6-trimethylphenyl)amino Cl 275–276° C. 79 B1a-2 N CN(2,6-ethylphenyl)amino Cl 80 B1a-2 N CN (2-oxomethyl-5-methyl- Clphenyl)amino 81 B1a-2 N CN (4-bromo-2,6-dimethyl- Cl phenyl)amino 82B1a-2 N CN (5-bromo-2,4,6-trimethyl- Cl phenyl)amino 83 B1a-2 N CN(2-ethyl-6-methylphenyl)amino Cl 84 B1a-2 N CN (2-broom-4,6-difluoro- Clphenyl)amino 85 B1a-2 N CN (2,4,6-trichlorophenyl)amino Cl 295–296° C.70 B1a-3 N CN (2,6-dichlorophenyl)amino Cl 268–269° C. 86 B1a-2 N CN(2,6-dichloro-4-trifluoromethyl- Cl 247–248° C. phenyl)amino 87 B1a-2 NCN (2,4-dichloro-6-trifluoromethyl- Cl 275–276° C. phenyl)amino 88 B1a-2N CN (2,4,6-tribromophenyl)amino Cl 292–294° C. 89 B1a-2 N CN(2,6-dibromo-4-methyl- Cl 283–284° C. phenyl)amino 90 B1a-2 N CN(2,6-dibromo-4-ipropyl- Cl 263–264° C. phenyl)amino 91 B1a-2 N OCH₃(4-methoxyphenyl)amino Cl 96 B22a C—Br CN (2,4,6-trimethylphenyl)aminoCOOCH₃ 71 B1c CH CN (4-cyano-2,6-dimethyl- COOCH₃ 258–259° C.phenyl)amino 97 B1c CH CN (4-cyano-2,6-dimethyl- COOH 258–259° C.phenyl)amino 98 B22b C—Br CN (2,4,6-trimethylphenyl)amino CONH₂ 73 B11cC—Br CN (4-cyano-2,6-dimethyl- CH₂Cl 238–240° C. phenyl)amino 74 B11dC—Br CN (4-cyano-2,6-dimethyl- CH₂NHCH₃ 223–224° C. phenyl)oxy 100 B11dC—Br CN (4-cyano-2,6-dimethyl- CH₂N(CH₃)₂ 189–191° C. phenyl)oxy 101B11d C—Br CN (4-cyano-2,6-dimethyl- CH₂NHCH₂CH 202–203° C. phenyl)oxy103 B2a N CN (2,6-dichlorophenyl)oxy Cl 104 B1b N CN(2-chloro-4-fluorophenyl)methyl Cl 201–202° C. 105 B1b N CN(2,4-dichlorophenyl)methyl Cl 191–192° C. 106 B1a N CN(2,6-dichlorophenyl)amino Cl 107 B1a-1 N CN (2,6-dimethylphenyl)amino Cl69 B1a-2 N CN (2-chloro-6-methylphenyl)amino Cl 108 B1a-2 N CN(2-ipropyl-6-methyl- Cl phenyl)amino 109 B1a-2 N CN(2,4-dichloro-6-methyl- Cl phenyl)amino 110 B1a-2 N CN(3-chloro-2,6-dimethyl- Cl 142–143° C. phenyl)amino 72 B2b N CN(2,4,6-trichlorophenyl)oxy Cl 238–239° C.

TABLE 2

Co. Ex. Physical data No. No. Z R² Q mp. 34 B19 N CN

155–157° C. 35 B18 N CN

168–173° C. 36 B14 N CN

37 B13 N CN

278–282° C. 38 B5d N CN C(═O)—NH₂ 262–263° C. 39 B1d CH CN

275–285° C. 5 B5 N CN CN 221–230° C. 40 B5b N C(═O)—NH₂ C(═O)—NH₂287–295° C. 41 B17 N C(═O)—NH₂

192–195° C. 42 B5c N

249–252° C. 11 B10a N CN

trifluoroacetate (1:1);  175° C. 1 B1 N CN Cl 243–244° C. 7 B7a N CNS—CH₃ 184–185° C. 8 B7b N CN S(═O)—CH₃ 219–221° C. 9 B8 N CN OCH₃198–199° C. 6 B6 N CN SH 254–255° C. 10 B9 N CN OH >300° C. 44 B10b N CN

45 B10b N CN

267–270° C. 4 B4 N CN

268–269° C. 46 B10b N CN

302–304° C. 47 B14 N CN

213–215° C. 48 B13 N CN

223–226° C. 49 B15 N CN F   196° C. 58 B8 N CN OC₂H₅ 302–304° C. 59 B10aN CN

196–197° C. 43 B1e N CN NH—O—CH₂—C═CH trifluoroacetate (1:1); 225–227°C. 68 B1e N CN

trifluoroacetate (1:1);>80° C.

TABLE 3

Co. Ex. Physical No. No. X R^(a) R^(b) R² Q data 50 B21a NH H CH₃ H COOH51 B21b NH H CH₃ H C(═O)—NH₂ 52 B20a O H CN H COOCH₃ 53 B20g O H CN HCOOH 54 B20c O H CN H C(═O)—NH—CH₃ 55 B20f O Br CN Br COOCH₃ 56 B20b O HCN H C(═O)—NH₂ 65 B20d O H CN H C(═O)—N(CH₃)₂ 95 B20e O Br CN H COOCH₃

TABLE 4

Co. Ex. Physical No. No. Z R² L Q data/mp. 92 B23 N 2,3-dichloro benzylSCH₃ 93 B23 N 3-trifluoromethyl benzyl SCH₃ 94 B23 N 3-trifluoromethylbenzyl OCH₃

C. PHARMACOLOGICAL EXAMPLE

The pharmacological activity of the present compounds was examined usingthe following test.

A rapid, sensitive and automated assay procedure was used for the invitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line,MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, 36,445-451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via the insitu reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was definedas the concentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:

${\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\mspace{14mu}{expressed}\mspace{14mu}{in}\mspace{14mu}\%},$whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% inhibitory concentration (IC₅₀ inμM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index(SI). Table 5 lists the IC₅₀, CC₅₀ and SI values for the compounds offormula (I).

TABLE 5 CC₅₀ Co. No. IC₅₀ (μM) (μM) SI 7 0.02 39.81 1990 90.01 >100 >10000 67 0.001995 >10 >5012 4 0.00158 39.81 25197 480.0079 >200 >12658 25 0.079 >100 >1266 20 0.002 3.981 1990 58 0.025150.12 1997 35 0.0631 50.12 794 33 0.00316 5.012 1586 380.00251 >100 >39841 5 0.01995 10 501 43 0.01585 63.096 3981 11 0.0025163.096 25138 68 0.01585 19.95 1259 19 0.001259 3.981 3162 2 0.00158550.12 31621 12 0.0040 >100 >25000 13 0.0040 >100 >25000 26 0.001 1.9951995 3 0.0501 >100 >1996 27 0.01 >10 >1000 14 0.0040 >10 2500 560.0631 >100 1585 16 0.0251 >100 >39841 65 0.07943 79.43 1000 62 0.00637.943 1261 61 0.00251 50.12 19968 63 0.00501 39.81 7946 66 0.00158531.62 19950 71 0.0251 >100 >3984 109 0.00398 12.59 3163 85 0.02 50.122506 89 0.00501 10 1996 98 0.00316 50.12 15861

1. A compound having the formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein-b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula—CH═CH—C(R^(2a))═CH—CH═  (b-1); q is 0, 1, 2; or where possible q is 3or 4; R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl; Lis C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby eachof said groups may be substituted with one or two substituentsindependently selected from C₃₋₇cycloalkyl, indolyl or isoindolyl, eachoptionally substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxyand C₁₋₆alkylcarbonyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein each of said aromatic rings may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the substituents defined in R²; or L is—X¹—R³ or —X²-Alk-R⁴ wherein Alk is C₁₋₄alkanediyl; R³ or R⁴ eachindependently are phenyl, pyridyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein each of said aromatic rings may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the substituents defined in R²; and X¹ or X²each independently are —NR⁷—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,—S(═O)_(p)—; Q represents cyano, hydroxy, mercapto, carboxyl, formyl,cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, mercaptoC₁₋₆alkyl, aminoC₁₋₆alkyl,mono- or di(C₁₋₄alkyl)-aminoC₁₋₆alkyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,C₁₋₆alkylS(═O)_(p), C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkenyloxyamino, R⁵—C(═O)—C₁₋₆alkyloxyamino, C₂₋₆alkynyl,polyhaloC₁₋₆alkyl, hydroxypolyhaloC₁₋₆alkyl, Het orC₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogen atom may optionally besubstituted with C₁₋₆alkyloxy; Z is C—Y wherein Y represents hydrogen,hydroxy, halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionallysubstituted with one or more halogen atoms, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms, C₁₋₆alkyl substituted withcyano or —C(═O)R⁸, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano,nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁸, —NH—S(═O)_(p)R⁸,—C(═O)R⁸, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁸, —C(═NH)R⁸ or aryl; R⁵ ishydrogen or a radical of formula

with A₁ in (d) being CH₂ or O; R⁶ is methyl, amino, mono- ordimethylamino or polyhalomethyl; R⁷ is hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy; C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted withC₁₋₆alkyloxycarbonyl; R⁸ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; p is 1 or 2; aryl is phenyl or phenyl substituted withone, two, three, four or five substituents each independently selectedfrom halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, tetrazolyl; Hetis imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,triazolyl, tetrazolyl optionally substituted with imino, a radical offormula (c) as described hereinabove, imidazolidinyl, pyrazolidinyl,thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl optionallysubstituted with hydroxy, isoxazolidinone, or a radical of formula

with A₂ in (e-1) being O, CH₂ or a direct bond; A₃ being CH₂ or NH; A₄being CH₂ or a direct bond; or A₃-A₄ representing CH═CH; R⁹ beinghydrogen or C₁₋₄alkylcarbonyl; provided that when Q is polyhaloC₁₋₆alkylthen Y is hydrogen or C₁₋₆alkyl; R^(2a) is cyano, aminocarbonyl, mono-or di(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano,aminocarbonyl or mono- or di(methyl)aminocarbonyl, C₂₋₆alkenylsubstituted with cyano, or C₂₋₆alkynyl substituted with cyano; each R²independently is hydroxy, halo, C₁₋₆alkyl optionally substituted withcyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substitutedwith one or more halogen atoms or cyano, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms or cyano, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

wherein each A₁ in (c) independently is N, CH or CR⁶; A₂ in (c) is NH,O, S or NR⁶; p is 1 or
 2. 2. A compound as claimed in claim 1, wherein Qis cyano, hydroxy, mercapto, carboxyl, hydroxyC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, aminocarbonyl, C₁₋₆alkyloxyC₁₋₆alkylwherein each hydrogen atom may optionally be substituted withC₁₋₆alkyloxy, C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkylS(═O),C₁₋₆alkyloxycarbonyl, polyhaloC₁₋₆alkyl, C₂₋₆alkenyloxyamino,R⁵—C(═O)—C₁₋₆alkyloxyamino, a radical of formula (c) or (e-1) or (e-2),imidazolyl, triazolyl, tetrazolyl optionally substituted with imino,isoxazolidinyl optionally substituted with hydroxy, isoxazolidinone. 3.A compound as claimed in claim 1, wherein L is —X¹—R³ wherein R³ is2,4,6-trisubstituted phenyl.
 4. A compound as claimed in claim 2,wherein L is —X¹—R³ wherein R³ is 2,4,6-trisubstituted phenyl.
 5. Acompound as claimed in claim 1, wherein the moiety in the 2 position ofthe pyrimidine ring is a 4-cyano-anilino group, L is —X¹—R³ wherein R³is a 2,4,6-trisubstituted phenyl, Z is C—Y with Y being halo or hydrogenand Q is hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, cyano or Het.
 6. Acompound as claimed in claim 2, wherein the moiety in the 2 position ofthe pyrimidine ring is a 4-cyano-anilino group, L is —X¹—R³ wherein R³is a 2,4,6-trisubstituted phenyl, Z is C—Y with Y being halo or hydrogenand Q is hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, cyano or Het.
 7. Acompound as claimed in claim 3, wherein the moiety in the 2 position ofthe pyrimidine ring is a 4-cyano-anilino group, L is —X¹—R³ wherein R³is a 2,4,6-trisubstituted phenyl, Z is C—Y with Y being halo or hydrogenand Q is hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, cyano or Het.
 8. Acompound as claimed in claim 4, wherein the moiety in the 2 position ofthe pyrimidine ring is a 4-cyano-anilino group, L is —X¹—R³ wherein R³is a 2,4,6-trisubstituted phenyl, Z is C—Y with Y being halo or hydrogenand Q is hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, cyano or Het.
 9. Acompound according to claim 1 wherein Q is hydroxyC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogenatom may optionally be substituted with C₁₋₆alkyloxy, carboxyl,C₁₋₆alkyloxycarbonyl, polyhaloC₁₋₆alkyl, aminocarbonyl, or imidazolyl.10. A compound according to claim 1 wherein Q is hydroxyC₁₋₆alkyl, mono-or di(C₁₋₄alkyl)aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl wherein eachhydrogen atom may optionally be substituted with C₁₋₆alkyloxy, carboxyl,C₁₋₆alkyloxycarbonyl, aminocarbonyl, or imidazolyl.
 11. A compound asclaimed in claim 1, wherein the compound is one of:4-[[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-hydroxymethyl]-2-pyrimidinyl]amino]benzonitrile;4-[[[6-trifluoromethyl-2-(4-cyanophenylamino)]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile;4-[[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-methoxymethyl]-2-pyrimidinyl]amino]benzonitrile;4-[[[5-bromo-4-(4-cyano-2,6-dibromophenoxy)-6-hydroxymethyl]2-pyrimidinyl]amino]benzonitrile;2-[(4-cyanophenyl)amino]-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinecarboxamide;5-bromo-2-[(4-cyanophenyl)amino]-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinecarboxamide; a N-oxide, a pharmaceutically acceptable addition salt, aquaternary amine and a stereochemically isomeric form thereof.
 12. Aprocess for preparing a compound as claimed in claim 1, characterized bya) reacting an intermediate of formula (II) with an amino derivative offormula (III) optionally under solvent-free conditions or in areaction-inert solvent under a reaction-inert atmosphere

 with W₁ being a suitable leaving group, and L, Q, Z, R¹, R², q and-b¹=b²-C(R^(2a))=b³-b⁴=as defined in claim 1; b) by reacting anintermediate of formula (III) with an intermediate of formula (IV) andan intermediate of formula (V) in the presence of a suitable solvent

 with W₁ being a suitable leaving group, Q, Z, R¹, R², q and-b¹=b²-C(R^(2a))=b³-b⁴=as defined in claim 1, and L_(a) beingC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, each of saidgroups being substituted with one or two substituents independentlyselected from C₃₋₇cycloalkyl; indolyl or isoindolyl, each optionallysubstituted with one, two, three or four substituents each independentlyselected from halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy andC₁₋₆alkylcarbonyl; phenyl, pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein each of said aromatic rings may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the substituents defined in R²; c) reactingan intermediate of formula (VI) with an intermediate of formula (VII)under solvent-free conditions or in an appropriate solvent under areaction-inert atmosphere

 with W₂ being a suitable leaving group, and Q, Z, R¹, R², R³, R⁷, q and-b¹=b²-C(R^(2a))=b³-b⁴=as defined in claim 1; d) reacting anintermediate of formula (VI) with an intermediate of formula (VIII) inan appropriate solvent under a reaction-inert atmosphere in the presenceof a suitable base

 with W₂ being a suitable leaving group, and Q, Z, R¹, R², q and-b¹=b²-C(R^(2a))=b³-b⁴=as defined in claim 1, and L_(b) being a radicalof formula —X¹—R³ or —X²-Alk-R⁴ with X¹, X², Alk, R³ and R⁴ as definedin claim 1; e) reacting an intermediate of formula (IX-a) with anintermediate of formula (X)

 with W₃ being a suitable leaving group and L, Z, R¹, R², q, A₂ and-b¹=b²-C(R^(2a))=b³-b⁴=as defined in claim 1; f) cyclizing anintermediate of formula (IX-b) in the presence of a suitable carbonicderivative and a suitable base

 with L, Z, R¹, R², R⁹, q, A₃, A₄ and -b¹=b²-C(R^(2a))=b³-b⁴=as definedin claim 1; g) reacting an intermediate of formula (IX-c) with acarbonic derivative in the presence of a suitable solvent

 with L, Z, R¹, R², R⁹, q, and -b¹=b²-C(R^(2a))=b³-b⁴=as defined inclaim 1; h) reacting an intermediate of formula (IX-d) withW₄—CH₂—CH₂—C(═O)—W₄ in the presence of a suitable base and a suitablesolvent

 with W₄ being a suitable leaving group and L, Z, R¹, R², q, and-b¹=b²-C(R^(2a))=b³-b⁴=as defined in claim 1; i) reacting anintermediate of formula (XXIII) with an intermediate of formula (XXIV)and (XXV) in the presence of a suitable base and a suitable solvent

 with L, Q, R¹, R², q, and -b¹=b²-C(R^(2a))=b³-b⁴=as defined in claim 1.13. A process as recited in claim 12, further comprising convertingcompounds of formula (I) into a therapeutically active non-toxic acidaddition salt by treatment with an acid.
 14. A process as recited inclaim 12, further comprising converting compounds of formula (I) into atherapeutically active non-toxic acid addition salt and converting theacid addition salt form into a free base by treatment with alkali.
 15. Aprocess as recited in claim 12, further comprising preparing at leastone of stereochemically isomeric forms, N-oxide forms, and quaternaryamines thereof.
 16. A pharmaceutical composition comprising apharmaceutically acceptable carrier and as active ingredient atherapeutically effective amount of a compound as claimed in claim 1.17. A process for preparing a pharmaceutical composition comprising:providing a therapeutically effective amount of a compound as claimed inclaim 1, and intimately mixing said therapeutically effective amount ofthe compound with a pharmaceutically acceptable carrier.
 18. A productcontaining (a) a compound as claimed in claim 1, and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in the treatment of HIV-1 infection.
 19. Apharmaceutical composition for use in the treatment of HIV-1 infectioncomprising a pharmaceutically acceptable carrier and as activeingredients (a) a compound as claimed in claim 1, and (b) anotherantiretroviral compound, as a combined preparation.
 20. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and asactive ingredient a therapeutically effective amount of a compound asclaimed in claim
 4. 21. A pharmaceutical composition comprising apharmaceutically acceptable carrier and as active ingredient atherapeutically effective amount of a compound as claimed in claim 2.22. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and as active ingredient a therapeutically effectiveamount of a compound as claimed in claim
 7. 23. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and asactive ingredient a therapeutically effective amount of a compound asclaimed in claim
 11. 24. A process for preparing a pharmaceuticalcomposition as claimed in claim 19 comprising: providing atherapeutically effective amount of a compound having the formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein-b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula—CH═CH—C(R^(2a))═CH—CH═(b-1); q is 0, 1, 2; or where possible q is 3 or4; R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; 1C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkyloxycarbonyl substituted with C₁₋₆alkyloxycarbonyl;L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, wherebyeach of said groups may be substituted with one or two substituentsindependently selected from C₃₋₇cycloalkyl, indolyl or isoindolyl, eachoptionally subsituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxyand C₁₋₆alkylcarbonyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein each of said aromatic rings may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the substituents defined in R²; or L is-X¹-R³ or —X²-Alk-R⁴ wherein Alk is C₁₋₄alkanediyl; R³ or R⁴ eachindependently are phenyl, pyridyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein each of said aromatic rings may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the substituents defined in R²; and X¹ or X²each independently are —NR⁷—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,—S(═O)_(p)—, O represents cyano, hydroxy, mercapto, carboxyl, formyl,cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, mercaptoC₁₋₆alkyl, aminoC₁₋₆alkyl,mono- or di(C₁₋₄alkyl)-aminoC₁₋₆alkyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,C₁₋₆alkylS(═O)_(p), C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkenyloxyamino, R⁵-C(═O)—C₁₋₆alkyloxyamino, C₂₋₆alkynyl,polyhaloC₁₋₆alkyl, hydroxypolyhaloC₁₋₆alkyl, Het orC₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogen atom may optionally besubstituted with C₁₋₆alkyloxy; Z is C-Y wherein Y represents hydrogen,hydroxy, halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionallysubstituted with one or more halogen atoms, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms, C₁₋₆alkyl substituted withcyano or —C(═O)R⁸, C₁₋₆akyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano,nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁸, —NH—S(═O)_(p)R⁸,—C(═O)R⁸, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁸, —C(═NH)R⁸ or aryl; R⁵ ishydrogen or a radical of formula

with A₁ in (d) being CH₂ or O; R⁶ is methyl, amino, mono- ordimethylamino or polyhalomethyl; R⁷ is hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy; C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted withC₁₋₆alkyloxycarbonyl; R⁸ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; p is 1 or 2; aryl is phenyl or phenyl substituted withone, two, three, four or five substituents each independently selectedfrom halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, tetrazolyl; Hetis imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,triazolyl, tetrazolyl optionally substituted with imino, a radical offormula (c) as described hereinabove, imidazolidinyl, pyrazolidinyl,thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl optionallysubstituted with hydroxy, isoxazolidinone, or a radical of formula

with A₂ in (e-1) being O, CH₂ or a direct bond; A₃ being CH₂ or NH; A₄being CH₂ or a direct bond; or A₃-A₄ representing CH═CH; R⁹ beinghydrogen or C₁₋₄alkylcarbonyl; provided that when O is polyhaloC₁₋₆alkylthen Y is hydrogen or C₁₋₆alkyl; R^(2a) is cyano, aminocarbonyl, mono-or di(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano,aminocarbonyl or mono- or di(methyl)aminocarbonyl, C₂₋₆alkenylsubstituted with cyano, or C₂₋₆alkylnyl substituted with cyano; each R²independently is hydroxy, halo, C₁₋₆alkyl optionally substituted withcyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substitutedwith one or more halogen atoms or cyano, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms or cyano, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

wherein each A₁ in (c) independently is N, CH or CR⁶, A₂ in (c) is NH,O, S or NR⁶; p is 1 or 2 and intimately mixing said therapeuticallyeffective amount of the compound with a pharmaceutically acceptablecarrier.
 25. A process for preparing a pharmaceutical composition asclaimed in claim 20 comprising: providing a therapeutically effectiveamount of a compound having the formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein—b¹=b²—C(R^(2a))=b³-b⁴=represents a bivalent radical of formula—CH═CH—C(R^(2a))═CH—CH═(b-1); q is 0, 1, 2; or where possible q is 3 or4; R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkyloxycarbonyl substituted with C₁₋₆alkyloxycarbonyl;wherein L is —X¹-R³ is 2,4,6-trisubstituted phenyl, wherein R³ isphenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each ofsaid aromatic rings may optionally be substituted with one, two, three,four or five substituents each independently selected from thesubstituents defined in R²; and X¹ is —NR⁷—, —NH—NH—, —N═N—, —O—,—C(═O)—, —CHOH—, —S—, —S(═O)_(p)—; wherein O is cyano, hydroxy,mercapto, carboxyl, hydroxyC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, aminocarbonyl, C₁₋₆alkyloxyC₁₋₆alkylwherein each hydrogen atom may optionally be substituted withC₁₋₆alkyloxy, C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkylS(═O),C₁₋₆alkyloxycarbonyl, polyhaloC₁₋₆alkyl, C₂₋₆alkenyloxyamino,R⁵—C(═O)—C₁₋₆alkyloxyamino, a radical of formula (c) or e-1) or (e-2),imidazolyl, traizolyl, tetrazolyl optionally substituted with imino,isoxazolidinyl optionally substituted with hydroxy, isoxazolidinone; Zis C-Y wherein Y represents hydrogen, hydroxy, halo, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms, C₂₋₆alkynyl optionally substituted with one or morehalogen atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁸,C₁₋₆akyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁸, —NH—S(═O)_(p)R⁸, —C(═O)R⁸, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁸, —C(═NH)R⁸ or aryl; R⁵ is hydrogen or a radicalof formula

with A₁ in (d) being CH₂ or O; R⁶ is methyl, amino, mono- ordimethylamino or polyhalomethyl; R⁷ is hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy; C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted withC₁₋₆alkyloxycarbonyl; R⁸ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; p is 1 or 2; aryl is phenyl or phenyl substituted withone, two, three, four or five substituents each independently selectedfrom halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, tetrazolyl; Hetis imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,triazolyl, tetrazolyl optionally substituted with imino, a radical offormula (c) as described hereinabove, imidazolidinyl, pyrazolidinyl,thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl optionallysubstituted with hydroxy, isoxazolidinone, or a radical of formula

with A₂ in (e-1) being O, CH₂ or a direct bond; A₃ being CH₂ or NH; A₄being CH₂ or a direct bond; or A₃-A₄ representing CH═CH; R⁹ beinghydrogen or C₁₋₄alkylcarbonyl; provided that when O is polyhaloC₁₋₆alkylthen Y is hydrogen or C₁₋₆alkyl; R^(2a) is cyano, aminocarbonyl, mono-or di(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano,aminocarbonyl or mono- or di(methyl)aminocarbonyl, C₂₋₆alkenylsubstituted with cyano, or C₂₋₆alkylnyl substituted with cyano; each R²independently is hydroxy, halo, C₁₋₆alkyl optionally substituted withcyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substitutedwith one or more halogen atoms or cyano, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms or cyano, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

wherein each A₁ in (c) independently is N, CH or CR⁶; A₂ in (c) is NH,O, S or NR⁶; p is 1 or 2 and intimately mixing said therapeuticallyeffective amount of the compound with a pharmaceutically acceptablecarrier.
 26. A process for preparing a pharmaceutical composition asclaimed in claim 21 comprising: providing a therapeutically effectiveamount of a compound having the formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein—b¹=b²—C(R^(2a))=b³-b⁴=represents a bivalent radical of formula—CH═CH—C(R^(2a))═CH—CH═(b-1); q is 0, 1, 2; or where possible q is 3 or4; R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkyloxycarbonyl substituted with C₁₋₆alkyloxycarbonyl;L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇-cycloalkyl, wherebyeach of said groups may be be substituted with one or two substituentsindependently selected from C₃₋₇cycloalkyl, indolyl or isoindolyl, eachoptionally substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxyand C₁₋₆alkylcrbonyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein each of said aromatic rings may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the substituents defined in R²; or L is—X¹-R³ or —X²-Alk-R⁴ wherein Alk is C₁₋₄alkanediyl; R³ or R⁴ eachindependently are phenyl, pyridyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein each of said aromatic rings may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the substituents defined in R²; and X¹ or X²each independently are —NR⁷—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,—S(═O)_(p)—; wherein Q is cyano, hydroxy, mercapto, carboxyl,hydroxyC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl, aminocarbonyl,C₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogen atom may optionally besubstituted with C₁₋₆alkyloxy, C₁₋₆alkyloxy, C₁₋₆alkylthio,C₁₋₆alkylS(═O), C₁₋₆alkyloxycarbonyl, polyhaloC₁₋₆alkyl,C₂₋₆alkenyloxyamino, R⁵—C(═O)—C₁₋₆alkyloxyamino, a radical of formula(c) or (e-1) or (e-2), imidazolyl, traizolyl, tetrazolyl optionallysubstituted with imino, isoxazolidinyl optionally substituted withhydroxy, isoxazolidinone; Z is C-Y wherein Y represents hydrogen,hydroxy, halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionallysubstituted with one or more halogen atoms, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms, C₁₋₆alkyl substituted withcyano or —C(═O)R⁸, C₁₋₆akyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano,nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁸, —NH—S(═O)_(p)R⁸,—C(═O)R⁸, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁸, —C(═NH)R⁸ or aryl; R⁵ ishydrogen or a radical of formula

with A₁ in (d) being CH₂ or O; R⁶ is methyl, amino, mono- ordimethylamino or polyhalomethyl; R⁷ is hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy; C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted withC₁₋₆alkyloxycarbonyl; R⁸ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; p is 1 or 2; aryl is phenyl or phenyl substituted withone, two, three, four or five substituents each independently selectedfrom halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, tetrazolyl; Hetis imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,triazolyl, tetrazolyl optionally substituted with imino, a radical offormula (c) as described hereinabove, imidazolidinyl, pyrazolidinyl,thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl optionallysubstituted with hydroxy, isoxazolidinone, or a radical of formula

with A₂ in (e-1) being O, CH₂ or a direct bond; A₃ being CH₂ or NH; A₄being CH₂ or a direct bond; or A₃-A₄ representing CH═CH; R⁹ beinghydrogen or C₁₋₄alkylcarbonyl; provided that when O is polyhaloC₁₋₆alkylthen Y is hydrogen or C₁₋₆alkyl; R^(2a) is cyano, aminocarbonyl, mono-or di(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano,aminocarbonyl or mono- or di(methyl)aminocarbonyl, C₂₋₆alkenylsubstituted with cyano, or C₂₋₆alkylnyl substituted with cyano; each R²independently is hydroxy, halo, C₁₋₆alkyl optionally substituted withcyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substitutedwith one or more halogen atoms or cyano, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms or cyano, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

wherein each A₁ in (c) independently is N, CH or CR⁶; A₂ in (c) is NH,O, S or NR⁶; p is 1 or 2 and intimately mixing said therapeuticallyeffective amount of the compound with a pharmaceutically acceptablecarrier.
 27. A process for preparing a pharmaceutical composition asclaimed in claim 22 comprising: providing a therapeutically effectiveamount of a compound having the formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein—b¹═b²—C(R^(2a))═b³—b⁴═ represents a bivalent radical of formula—CH═CH—C(R^(2a))═CH—CH═(b-1); q is 0, 1, 2; or where possible q is 3 or4; R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;C₁₋₆alkyloxyC₁₋₆alkyloxycarbonyl substituted with C₁₋₆alkyloxycarbonyl;wherein the moiety in the 2 position of the pyrimidine ring is a 4-cyanoanilino group, L is —Z¹R³ wherein R³ is a 2,4,6-trisubstituted phenyl, Zis C—Y with Y being halo or hydrogen and Q is hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, cyano or Het R³ or R⁴ each independently arephenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each ofsaid aromatic rings may optionally be substituted with one, two, three,four or five substituents each independently selected from thesubstituents defined in R²; and X¹ or X² each independently are —NR⁷—,—NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)_(p)—; Q representscyano, hydroxy, mercapto, carboxyl, formyl, cyano C₁₋₆alkyl,hydroxyC₁₋₆alkyl, mercaptoC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,C₁₋₆alkylS(═O)_(p), C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkenyloxyamino, R⁵ —C(═O)-C₁₋₆alkyloxyamino, C₂₋₆alkynyl,polyhaloC₁₋₆alkyl, hydroxypolyhaloC₁₋₆alkyl, Het orC₁₋₆alkyloxyC₁₋₆alkyl wherein each hydrogen atom may optionally besubstituted with C₁₋₆alkyloxy; R⁵ is hydrogen or a radical of formula

with A₁ in (d) being CH₂ or O; R⁶ is methyl, amino, mono- ordimethylamino or polyhalomethyl; R⁷ is hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy; C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted withC₁₋₆alkyloxycarbonyl; R⁸ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; p is 1 or 2; aryl is phenyl or phenyl substituted withone, two, three, four or five substituents each independently selectedfrom halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, tetrazolyl; Hetis imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,triazolyl, tetrazolyl optionally substituted with imino, a radical offormula (c) as described hereinabove, imidazolidinyl, pyrazolidinyl,thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl optionallysubstituted with hydroxy, isoxazolidinone, or a radical of formula

with A₂ in (e-1) being O, CH₂ or a direct bond; A₃ being CH₂ or NH; A₄being CH₂ or a direct bond; or A₃-A₄ representing CH═CH; R⁹ beinghydrogen or C₁₋₄alkylcarbonyl; R^(2a) is cyano, aminocarbonyl, mono- ordi(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano, aminocarbonylor mono- or di(methyl)aminocarbonyl, C₂₋₆alkenyl substituted with cyano,or C₂₋₆alkylnyl substituted with cyano; each R² independently ishydroxy, halo, C₁₋₆alkyl optionally substituted with cyano or —C(═O)R⁶,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms or cyano, C₂₋₆alkynyl optionally substituted with one ormore halogen atoms or cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,—NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶or a radical of formula

wherein each A₁ in (c) independently is N, CH or CR⁶; A₂ in (c) is NH,O, S or NR⁶; p is 1 or 2 and intimately mixing said therapeuticallyeffective amount of the compound with a pharmaceutically acceptablecarrier.
 28. A process for preparing a pharmaceutical composition asclaimed in claim 23 comprising: providing a therapeutically effectiveamount of a compound selected from the group consisting of:4[[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-hydroxymethyl]-2-pyrimidinyl]amino]benzonitrile;4-[[[6-trifluoromethyl-2-(4-cyanophenylamino)]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile;4-[[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-methoxymethyl]-2pyrimidinyl]amino]benzonitrile;4-[[[5-bromo-4-(4-cyano-2,6-dibromophenoxy)-6-hydroxymethyl]2-pyrimidinyl]amino]benzonitrile;2-[(4-cyanophenyl)amino]-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinecarboxyamide;5-bromo-2-[(4-cyanophenyl)amino]-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinecarboxamide; and N-oxide, pharmaceutically acceptable addition salts,quaternary amine and stereochemically isomeric forms thereof, andintimately mixing said therapeutically effective amount of the compoundwith a pharmaceutically acceptable carrier.
 29. A product containing (a)a compound as claimed in claim 2, and (b) another antiretroviralcompound, as a combined preparation for simultaneous, separate orsequential use in the treatment of HIV-1 infection.
 30. A productcontaining (a) a compound as claimed in claim 3, and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in the treatment of HIV-1 infection.
 31. Aproduct containing (a) a compound as claimed in claim 4, and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in the treatment of HIV-1 infection.
 32. Aproduct containing (a) a compound as claimed in claim 5, and (b) anotherantiretroviral compound, as separate preparations for simultaneous,separate or sequential use in the treatment of HIV-1 infection.
 33. Aproduct containing (a) a compound as claimed in claim 6, and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in the treatment of HIV-1 infection.
 34. Aproduct containing (a) a compound as claimed in claim 7, and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in the treatment of HIV-1infection.
 35. Aproduct containing (a) a compound as claimed in claim 8, and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in the treatment of HIV-1 infection.
 36. Aproduct containing (a) a compound as claimed in claim 11, and (b)another antiretroviral compound, as a combined preparation forsimultaneous, separate or sequential use in the treatment of HIV-1infection.
 37. A pharmaceutical composition for use in treatment ofHIV-1 infection comprising a pharmaceutically acceptable carrier and asactive ingredients (a) a compound as claimed in claim 2, and (b) anotherantiretroviral compound, as a combined preparation.
 38. A pharmaceuticalcomposition for use in treatment of HIV-1 infection comprising apharmaceutically acceptable carrier and as active ingredients (a) acompound as claimed in claim 3, and (b) another antiretroviral compound,as a combined preparation.
 39. A pharmaceutical composition for use intreatment of HIV-1 infection comprising a pharmaceutically acceptablecarrier and as active ingredients (a) a compound as claimed in claim 4,and (b) another antiretroviral compound, as a combined preparation. 40.A pharmaceutical composition for use in treatment of HIV-1 infectioncomprising a pharmaceutically acceptable carrier and as activeingredients (a) a compound as claimed in claim 5, and (b) anotherantiretroviral compound, as a combined preparation.
 41. A pharmaceuticalcomposition for use in treatment of HIV-1 infection comprising apharmaceutically acceptable carrier and as active ingredients (a) acompound as claimed in claim 6, and (b) another antiretroviral compound,as a combined preparation.
 42. A pharmaceutical composition for use intreatment of HIV-1 infection comprising a pharmaceutically acceptablecarrier and as active ingredients (a) a compound as claimed in claim 7,and (b) another antiretroviral compound, as a combined preparation. 43.A pharmaceutical composition for use in treatment of HIV-1 infectioncomprising a pharmaceutically acceptable carrier and as activeingredients (a) a compound as claimed in claim 8, and (b) anotherantiretroviral compound, as a combined preparation.
 44. A pharmaceuticalcomposition for use in treatment of HIV-1 infection comprising apharmaceutically acceptable carrier and as active ingredients (a) acompound as claimed in claim 11, and (b) another antiretroviralcompound, as a combined preparation.
 45. A method for the treatment ofHIV-1 infection, comprising: providing an active ingredient, andadministering an effective amount of a composition comprising saidactive ingredient to a human being in need thereof wherein said activeingredient comprises a compound as claimed in claim
 1. 46. A method forthe treatment of HIV-1 infection, comprising: providing an activeingredient, and administering an effective amount of a compositioncomprising said active ingredient to a human being in need thereofwherein said active ingredient comprises a compound as claimed in claim4.
 47. A method for the treatment of HIV-1 infection, comprising:providing an active ingredient, and administering an effective amount ofa composition comprising said active ingredient to a human being in needthereof wherein said active ingredient comprises a compound as claimedin claim
 2. 48. A method for the treatment of HIV-1 infection,comprising: providing an active ingredient, and administering aneffective amount of a composition comprising said active ingredient to ahuman being in need thereof wherein said active ingredient comprises acompound as claimed in claim
 7. 49. A method for the treatment of HIV-1infection, comprising: providing an active ingredient, and administeringan effective amount of a composition comprising said active ingredientto a human being in need thereof wherein said active ingredientcomprises a compound as claimed in claim 11.